Multibinding inhibitors of microsomal triglyceride transferase protein

Abstract

Disclosed are multibinding compounds which inhibit microsomal triglyceride transferase protein (MTP), a protein which mediates the transfer of lipids during the assembly of lipoproteins and related biomolecules. The multibinding compounds contain from 2 to 10 ligands covalently attached to one or more linkers. The multibinding compounds of this invention are useful for lowering serum lipid, cholesterol and/or triglyceride levels, and for preventing and treating disorders associated with hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholestrolemia, hypertriglyceridemia and the like, such atherosclerosis.

What is claimed is:  
     
         1 . A multibinding compound of formula I:  
       (L) p (X) q   I  
       wherein each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from 1 to 20; and each L is independently a ligand selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein 
 each W is a divalent radical independently selected from the group consisting of:  
                     
 each R 1  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and a covalent bond linking the ligand to a linker;  
 each R 2  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and a covalent bond linking the ligand to a linker;  
 each R 3  is independently selected from the group consisting of hydrogen, alkyl and halo;  
 each R 4  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl and a covalent bond linking the ligand to a linker;  
 each R 5  is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, suostituted amino and a covalent bond linking the ligand to a linker; or R 4  and R 5  may be joined, together with the >NC(O)— group to which they are attached, to form a heterocyclic ring;  
 each R 6  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and a covalent bond linking the ligand to a linker;  
 each R 7  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, a covalent bond linking the ligand to a linker and —NR 14 R 15 , where R 14  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl and heteroaryl; and R 15  is a covalent bond linking the ligand to a linker;  
 each R 8  is independently selected from the group consisting of hydrogen, acyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, a covalent bond linking the ligand to a linker  
 each R 9  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, a covalent bond linking the ligand to a linker and —NR 14 R 15 , where R 14  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl and heteroaryl; and R 15  is a covalent bond linking the ligand to a linker;  
 each R 10 , R 11 , R 12  and R 13  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryl, aryloxy, halo, heteroaryl, heteroaryloxy, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, acyloxy, aminoacyl, aminocarbonyl, —S(O)R 16  and —SO 2 R 16 , where each R 16  is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl and heteroaryl;  
 each ring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;  
 each ring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;  
 each ring C, together with the nitrogen atom to which it is attached, forms a heterocyclic ring;  
 each Q is independently selected from the group consisting of a covalent bond, —O—, —S—, —S(O)—, —SO,—, alkylene, substituted alkylene, alkenylene, substituted alkenylene and —NR 17 —, where R 17  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl and heteroaryl;  
 each a is independently an integer of from 2 to 6;  
 each b is independently an integer of from 0 to 6;  
 each c is independently an integer of from 2 to 4;  
 and pharmaceutically-acceptable salts or pro-drugs thereof;  
 provided that when p is 2, q is 1 and a first ligand has formula IA or IB, where R 1  or R 2  is a covalent bond linking the first ligand to the linker, then a second ligand does not have formula ID or IE, where R 8  or R 9  are a covalent bond linking the second ligand to the linker.  
 
     
     
         2 . The multibinding compound of  claim 1 , wherein q is less than p.  
     
     
         3 . The multibinding compound of  claim 1 , wherein W is a divalent radical having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 each R 18  and R 19  are independently selected from the group consisting of hydrogen or halo; and  
 Q′ is a covalent bond, —O— or —S—.  
 
     
     
         4 . The multibinding compound of  claim 1 , wherein each R 5  group is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl and substituted cycloalkyl.  
     
     
         5 . The multibinding compound of  claim 4 , wherein each R 5  group is substituted with from 1 to 4 substituents and one of the substituents is attached to the ring atom in the position adjacent to the atom attached to the —C(O)— group.  
     
     
         6 . The multibinding compound of  claim 5 , wherein each R 5  is a 2-(4′-trifluoromethylphenyl)phenyl group.  
     
     
         7 . The multibinding compound of  claim 1 , wherein each ring C forms a piperidine or a 1,2,3,4-tetrahydroisoquinoline ring.  
     
     
         8 . The multibinding compound of  claim 1 , wherein each linker independently has the formula:  
       —X a —Z—(Y a —Z) m —Y b —Z—X a — 
       wherein 
 m is an integer of from 0 to 20;  
 X a  at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;  
 Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;  
 Y a  and Y b  at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —N═C(X a )—NR′—, —P(O)(OR′)—O—, —S(O) n CR′R″—, —S(O) n —NR′—, —S—S— and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.  
 
     
     
         9 . A multibinding compound of formula II:  
       L′—X′—L′  II  
       wherein X′ is a linker; and each L′ is a ligand independently selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein 
 each R 20  and R 21  is independently selected from the group consisting of hydrogen and halo;  
 each R 22  is independently selected from the group consisting of hydrogen, alkyl and halo;  
 each R 23  is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;  
 each R 24  is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;  
 each R 25  is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl, substituted cycloalkyl and a covalent bond linking the ligand to the linker;  
 each R 26  is independently selected from the group consisting of hydrogen, alkyl and a covalent bond linking the ligand to the linker;  
 each R 27  is independently selected from the group consisting of hydrogen, a covalent bond linking the ligand to a linker and —NR 30 R 31 , where R 30  is selected from the group consisting of hydrogen and alkyl; and R 31  is a covalent bond linking the ligand to a linker;  
 each R 28  is a covalent bond linking the ligand to a linker;  
 each R 29  is independently selected from the group consisting of a covalent bond linking the ligand to a linker and —NR 30 R 31 , where R 30  is selected from the group consisting of hydrogen and alkyl; and R 31  is a covalent bond linking the ligand to a linker;  
 each Q″ is independently selected from the group consisting of a covalent bond, —O— and —S— 
 each a is independently an integer of from 2 to 6;  
 each b is independently an integer of from 0 to 6;  
 and pharmaceutically-acceptable salts or pro-drugs thereof;  
 provided that in each ligand only one of R 23 , R 24 , R 25 , R 26 , R 27 , R 28  and R 29  is a covalent bond linking the ligand to the linker;  
 and further provided that when a first ligand has formula IIA or IIB, where R 23  is a covalent bond linking the first ligand to the linker, then a second ligand does not have formula IID or IIE, where R 28  or R 29  are a covalent bond linking the second ligand to the linker.  
 
     
     
         10 . The multibinding compound of  claim 9 , wherein each R 25  group is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl and substituted cycloalkyl.  
     
     
         11 . The multibinding compound of  claim 10 , wherein each R 25  group is substituted with from 1 to 4 substituents and one of the substituents is attached to the ring atom in the position adjacent to the atom attached to the —C(O)— group.  
     
     
         12 . The multibinding compound of  claim 11 , wherein each R 25  is a 2-(4′-trifluoromethylphenyl)phenyl group.  
     
     
         13 . The multibinding compound of  claim 9 , wherein each linker independently has the formula:  
       —X a —Z—(Y a —Z) m —Y b —Z—X a — 
       where 
 m is an integer of from 0 to 20;  
 X a  at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;  
 Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;  
 Y a  and Y b  at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —N═C(X a )—NR′—, —P(O)(OR′)—O—, —S(O) n CR′R″—, —S(O) n —NR′—, —S—S— and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.  
 
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formula I:  
       (L) p (X) q   I  
       wherein each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from 1 to 20; and each L is independently a ligand selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein 
 each W is a divalent radical independently selected from the group consisting of:  
                     
 each R 1  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and a covalent bond linking the ligand to a linker;  
 each R 2  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and a covalent bond linking the ligand to a linker;  
 each R 3  is independently selected from the group consisting of hydrogen, alkyl and halo;  
 each R 4  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl and a covalent bond linking the ligand to a linker;  
 each R 5  is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, substituted amino and a covalent bond linking the ligand to a linker; or R 4  and R 5  may be joined, together with the >NC(O)— group to which they are attached, to form a heterocyclic ring;  
 each R 6  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and a covalent bond linking the ligand to a linker;  
 each R 7  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, a covalent bond linking the ligand to a linker and —NR 14 R 15 , where R 14  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl and heteroaryl; and R 15  is a covalent bond linking the ligand to a linker;  
 each R 8  is independently selected from the group consisting of hydrogen, acyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, a covalent bond linking the ligand to a linker  
 each R 9  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, a covalent bond linking the ligand to a linker and —NR 14 R 15 , where R 14  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl and heteroaryl; and R 15  is a covalent bond linking the ligand to a linker;  
 each R 10 , R 11 , R 12  and R 13  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryl, aryloxy, halo, heteroaryl, heteroaryloxy, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, acyloxy, aminoacyl, aminocarbonyl, —S(O)R 16  and —SO 2 R 16 , where each R 16  is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyi, cycloalkyl, substituted cycloalkyl, aryl and heteroaryl;  
 each ring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;  
 each ring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl heteroaryl and heterocyclic;  
 each ring C, together with the nitrogen atom to which it is attached, forms a heterocyclic ring;  
 each Q is independently selected from the group consisting of a covalent bond, —O—, —S—, —S(O)—, —SO 2 —, alkylene, substituted alkylene, alkenylene, substituted alkenylene and —NR 17 —, where R 17  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl and heteroaryl;  
 each a is independently an integer of from 2 to 6;  
 each b is independently an integer of from 0 to 6;  
 each c is independently an integer of from 2 to 4;  
 and pharmaceutically-acceptable salts or pro-drugs thereof;  
 provided that when p is 2, q is 1 and a first ligand has formula IA or IB, where R 1  or R 2  is a covalent bond linking the first ligand to the linker, then a second ligand does not have formula ID or IE, where R 8  or R 9  are a covalent bond linking the second ligand to the linker.  
 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein q is less than p.  
     
     
         16 . The pharmaceutical composition of  claim 14 , wherein W is a divalent radical having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 each R 18  and R 19  are independently selected from the group consisting of hydrogen or halo; and  
 Q′ is a covalent bond, —O— or —S.  
 
     
     
         17 . The pharmaceutical composition of  claim 14 , wherein each R 5  group is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl and substituted cycloalkyl.  
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein each R 5  group is substituted with from 1 to 4 substituents and one of the substituents is attached to the ring atom in the position adjacent to the atom attached to the —C(O)— group.  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein each R 5  is a 2-(4′-trifluoromethylphenyl)phenyl group.  
     
     
         20 . The pharmaceutical composition of  claim 14 , wherein each ring C forms a piperidine or a 1,2,3,4-tetrahydroisoquinoline ring.  
     
     
         21 . The pharmaceutical composition of  claim 14 , wherein each linker independently has the formula:  
       —X a —Z—(Y a —Z) m —Y b —Z—X a — 
       wherein 
 m is an integer of from 0 to 20;  
 X a  at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;  
 Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;  
 Y a  and Y b  at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —N═C(X a )—NR′—, —P(O)(OR′)—O—, —S(O) n CR′R″—, —S(O) n —NR′—, —S—S— and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.  
 
     
     
         22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formula II:  
       L′—X′—L′  II  
       wherein X′ is a linker; and each L′ is a ligand independently selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein 
 each R  20  and R 21  is independently selected from the group consisting of hydrogen and halo;  
 each R 22  is independently selected from the group consisting of hydrogen, alkyl and halo;  
 each R 23  is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;  
 each R 24  is independently selected from the group consisting of hydrogen and a covalent bond linking the ligand to the linker;  
 each R  25  is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl, substituted cycloalkyl and a covalent bond linking the ligand to the linker;  
 each R 26  is independently selected from the group consisting of hydrogen, alkyl and a covalent bond linking the ligand to the linker;  
 each R 27  is independently selected from the group consisting of hydrogen, a covalent bond linking the ligand to a linker and —NR 30 R 31 , where R 30  is selected from the group consisting of hydrogen and alkyl; and R 31  is a covalent bond linking the ligand to a linker;  
 each R 28  is a covalent bond linking the ligand to a linker;  
 each R 29  is independently selected from the group consisting of a covalent bond linking the ligand to a linker and —NR 30 R 31 , where R 30  is selected from the group consisting of hydrogen and alkyl; and R 31  is a covalent bond linking the ligand to a linker;  
 each Q″ is independently selected from the group consisting of a covalent bond, —O— and —S— 
 each a is independently an integer of from 2 to 6;  
 each b is independently an integer of from 0 to 6;  
 and pharmaceutically-acceptable salts or pro-drugs thereof;  
 provided that in each ligand only one of R 23 , R 24 , R 25 , R 26 , R 27 , R 28  and R 29  is a covalent bond linking the ligand to the linker;  
 and further provided that when a first ligand has formula IIA or IIB, where R 23  is a covalent bond linking the first ligand to the linker, then a second ligand does not have formula IID or IIE, where R 28  or R 29  are a covalent bond linking the second ligand to the linker.  
 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein each R 25  group is independently selected from the group consisting of aryl, heteroaryl, heterocyclic, cycloalkyl and substituted cycloalkyl.  
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein each R 25  group is substituted with from 1 to 4 substituents and one of the substituents is attached to the ring atom in the position adjacent to the atom attached to the —C(O)— group.  
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein each R 25  is a 2-(4′-trifluoromethylphenyl)phenyl group.  
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein each linker independently has the formula:  
       —X a —Z—(Y a —Z) m —Y b —Z—X a — 
       wherein 
 m is an integer of from 0 to 20;  
 X a  at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S), —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;  
 Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;  
 Y a  and Y b  at each separate occurrence are selected from the group consisting of —C(O)NR′—, —NR′C(O)—, —NR′C(O)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —NR′—C(O)—O—, —N═C(X a )—NR′—, —P(O)(OR′)—O—, —S(O) n CR′R″—, —S(O) n —NR′—, —S—S— and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.  
 
     
     
         27 . A method for preventing or treating atherosclerosis in a patient, the method comprising administering to a patient with atherosclerosis or at risk for developing atherosclerosis a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound of claims  1  or  9 .  
     
     
         28 . A method for lowering serum lipid, cholesterol and/or triglyceride levels in a patient, the method comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound of claims  1  or  9 .  
     
     
         29 . A method for preventing or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholestrolemia, hypertriglyceridemia, pancreatitis, diabetes and/or obsesity in a patient, the method comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound of claims  1  or  9 .  
     
     
         30 . A method for identifying multimeric ligand compounds possessing multibinding properties for microsomal triglyceride transferase protein, which method comprises: 
 (a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality    (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;    (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and    (d) assaying the multimeric ligand compounds produced in the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties for microsomal triglyceride transferase protein.    
     
     
         31 . A method for identifying multimeric ligand compounds possessing multibinding properties for microsomal triglyceride transferase protein, which method comprises: 
 (a) identifying a library of ligands wherein each ligand contains at least one reactive functionality:    (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;    (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and    (d) assaying the multimeric ligand compounds produced in the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties for microsomal triglyceride transferase protein.    
     
     
         32 . The method according to  claim 30  or  31 , wherein the preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b).  
     
     
         33 . The method according to  claim 32 , wherein the multimeric ligand compounds comprising the multimeric ligand compound library are dimeric.  
     
     
         34 . The method according to  claim 33 , wherein the dimeric ligand compounds comprising the dimeric ligand compound library are heterodimeric.  
     
     
         35 . The method according to  claim 34 , wherein the heterodimeric ligand compound library is prepared by sequential addition of a first and second ligand.  
     
     
         36 . The method according to  claim 30  or  31 , wherein, prior to procedure (d), each member of the multimeric ligand compound library is isolated from the library.  
     
     
         37 . The method according to  claim 36 , wherein each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).  
     
     
         38 . The method according to  claim 30  or  claim 31 , wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability and amphiphilic linkers.  
     
     
         39 . The method according to  claim 38 , wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.  
     
     
         40 . The method according to  claim 39 , wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å.  
     
     
         41 . The method according to  claim 30  or  31 , wherein the tigand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.  
     
     
         42 . The method according to  claim 41 , wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.  
     
     
         43 . The method according to  claim 30  or  claim 31 , wherein the multimeric ligand compound library comprises homomeric ligand compounds.  
     
     
         44 . The method according to  claim 30  or  claim 31 , wherein the multimeric ligand compound library comprises heteromeric ligand compounds.  
     
     
         45 . A library of multimeric ligand compounds which may possess multivalent properties for microsomal triglyceride transferase protein, which library is prepared by the method comprising: 
 (a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality;    (b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and    (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.    
     
     
         46 . A library of multimeric ligand compounds which may possess multivalent properties for microsomal triglyceride transferase protein, which library is prepared by the method comprising: 
 (a) identifying a library of ligands wherein each ligand contains at least one reactive functionality;    (b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and    (c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.    
     
     
         47 . The library according to  claim 45  or  claim 46 , wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability and amphiphilic linkers.  
     
     
         48 . The library according to  claim 47 , wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.  
     
     
         49 . The library according to  claim 48 , wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å.  
     
     
         50 . The library according to  claim 45  or  46 , wherein the ligand or mixture of ligands is selected to have reactive functionaiiLy at different sites on said ligands.  
     
     
         51 . The library according to  claim 50 , wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.  
     
     
         52 . The library according to  claim 45  or  claim 46 , wherein the multimeric ligand compound library comprises homomeric ligand compounds.  
     
     
         53 . The library according to  claim 45  or  claim 46 , wherein the multimeric ligand compound library comprises heteromeric ligand compounds.  
     
     
         54 . An iterative method for identifying multimeric ligand compounds possessing multibinding properties for microsomal triglyceride transferase protein, which method comprises: 
 (a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands;    (b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties for microsomal triglyceride transferase protein;    (c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties for microsomal triglyceride transferase protein;    (d) evaluating what molecular constraints imparted or are consistent with imparting multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)-(c) above;    (e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration;    (f) evaluating what molecular onstraints imparted or are consistent with imparting enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above;    (g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints.    
     
     
         55 . The method according to  claim 54 , wherein steps (e) and (f) are repeated from 2-50 times.  
     
     
         56 . The method according to  claim 55  wherein steps (e) and (f) are repeated from 5-50 times.