Non-peptidic cyclophilin binding compounds and their use

Abstract

The invention relates to non-peptidic compounds that possess bioactive properties, such as the ability to protect neuronal cells from otherwise lethal treatments or the ability to promote the growth or regeneration of neuronal cells. In part, the invention provides compounds that interact with or bind to a cyclophilin and compounds that have activity towards neuronal cells. Methods for using the compounds, such as administering them to cells or animals or using them to treat neurodegenerative conditions, are specifically included.

We claim:  
     
         1 . A method of using a compound to bind a cyclophilin-type immunophilin protein, comprising contacting the compound with a cyclophilin, wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
         where n in C n  is 0 or 1;  
         the dashed bond symbol represents an optional bond;  
         X and Y may independently be N, NH, O, S, or a direct bond;  
         R 1  is the same or different from R 2 , and either can be 
 one or more C1-C6 branched or straight chain alkyl or alkenyl groups;  
 one or more C1-C3 branched or straight chain alkyl groups substituted by one or more Q groups;  
 or one or more Q groups, 
 where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof;  
 
 
         and R 3  may be one to three substituents selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, Q as defined above, or a combination thereof.  
       
     
     
         2 . The method of  claim 1 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         3 . The method of  claim 2 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         4 . The method of  claim 1 , wherein contacting the compound with a cyclophilin occurs in vivo.  
     
     
         5 . The method of  claim 1 , wherein contacting the compound with a cyclophilin occurs within a cell or in a cell culture.  
     
     
         6 . The method of  claim 1 , wherein the cyclophilin protein is a human cyclophilin.  
     
     
         7 . The method of  claim 1 , wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.  
     
     
         8 . The method of  claim 7 , wherein the animal is a human.  
     
     
         9 . The method of  claim 8 , wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.  
     
     
         10 . The method of  claim 8 , wherein the human has Parkinson's disease, Alzheimer's disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.  
     
     
         11 . A complex comprising a compound of Formula I of  claim 1  and a cyclophilin.  
     
     
         12 . The complex of  claim 11 , wherein the cyclophilin is a human cyclophilin.  
     
     
         13 . A composition comprising a compound of Formula I of  claim 1 , further comprising a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         14 . A method of using a compound of Formula I of  claim 1 , comprising administering a pharmaceutically effective amount of the compound to an animal.  
     
     
         15 . The method of  claim 14 , wherein the animal is a human.  
     
     
         16 . The method of  claim 15 , wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.  
     
     
         17 . The method of  claim 15 , wherein the human has Parkinson's disease, Alzheimer's disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.  
     
     
         18 . A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of the composition of  claim 13 .  
     
     
         19 . A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of the composition of  claim 13 .  
     
     
         20 . A method of protecting nerves from damage comprising administering to an animal an effective amount of the composition of  claim 13 .  
     
     
         21 . A method of using a compound to bind a cyclophilin-type immunophilin protein, comprising contacting the compound with a cyclophilin, wherein the compound has the following formula:  
       
         
           
           
               
               
           
         
         where R 4  and R 5  may independently be 
 —N—SO 2 —R,  
 —SO 2 —NRR,  
 —O—R,  
 —CO—N—R,  
 —N—CO—R,  
 —CO—R,  
 
         wherein each R may independently be 
 hydrogen, Q, or a C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO 2 , N, or NH;  
 where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.  
 
       
     
     
         22 . The method of  claim 21 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         23 . The method of  claim 21 , wherein each R of R 4  and R 5  in said compound of Formula II may independently be 
 hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;    where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.    
     
     
         24 . The method of  claim 23 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         25 . The method of  claim 21 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         26 . The method of  claim 23 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         27 . The method of  claim 21 , wherein contacting the compound with a cyclophilin occurs in vivo.  
     
     
         28 . The method of  claim 23 , wherein contacting the compound with a cyclophilin occurs in vivo.  
     
     
         29 . The method of  claim 21 , wherein contacting the compound with a cyclophilin occurs within a cell.  
     
     
         30 . The method of  claim 23 , wherein contacting the compound with a cyclophilin occurs within a cell.  
     
     
         31 . The method of  claim 21 , wherein the cyclophilin is a human cyclophilin.  
     
     
         32 . The method of  claim 23 , wherein the cyclophilin is a human cyclophilin.  
     
     
         33 . The method of  claim 21 , wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.  
     
     
         34 . The method of  claim 23 , wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.  
     
     
         35 . The method of  claim 33 , wherein the animal is human  
     
     
         36 . The method of  claim 34 , wherein the animal is human.  
     
     
         37 . The method of  claim 35 , wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.  
     
     
         38 . The method of  claim 36 , wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.  
     
     
         39 . The method of  claim 35 , wherein the human has Parkinson's disease, Alzheimer's disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.  
     
     
         40 . The method of  claim 36 , wherein the human has Parkinson's disease, Alzheimer's disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.  
     
     
         41 . A complex comprising a compound of Formula II of  claim 21  and a cyclophilin.  
     
     
         42 . The complex of  claim 41  wherein each R of R 4  and R 5  in said compound of Formula II may independently be 
 hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;  
 where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.  
 
     
     
         43 . The complex of  claim 41 , wherein the cyclophilin is a human cyclophilin.  
     
     
         44 . The complex of  claim 42 , wherein the cyclophilin is a human cyclophilin.  
     
     
         45 . A composition comprising a compound of Formula II of  claim 21 , further comprising a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         46 . The composition of  claim 45 , wherein each R of R 4  and R 5  in said compound of Formula II may independently be 
 hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;    where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.    
     
     
         47 . A method of using a compound of Formula II of  claim 21 , comprising administering a pharmaceutically effective amount of the compound to an animal.  
     
     
         48 . The method of  claim 47 , wherein each R of R 4  and R 5  in said compound of Formula II may independently be 
 hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;    where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.    
     
     
         49 . The method of  claim 47 , wherein the animal is human.  
     
     
         50 . The method of  claim 48 , wherein the animal is human.  
     
     
         51 . The method of  claim 49 , wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.  
     
     
         52 . The method of  claim 50 , wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.  
     
     
         53 . The method of  claim 49 , wherein the human has Parkinson's disease, Alzheimer's disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.  
     
     
         54 . The method of  claim 50 , wherein the human has Parkinson's disease, Alzheimer's disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy including diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.  
     
     
         55 . A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of the composition of  claim 45 .  
     
     
         56 . A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of the composition of  claim 46 .  
     
     
         57 . A method of protecting nerves from damage comprising administering to an animal an effective amount of the composition of  claim 45 .  
     
     
         58 . A method of protecting nerves from damage comprising administering to an animal an effective amount of the composition of  claim 46 .  
     
     
         59 . A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of the composition of  claim 45 .  
     
     
         60 . A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of the composition of  claim 46 .  
     
     
         61 . A method of identifying a cyclophilin binding compound, comprising selecting one or more R 1-5 , X, and Y groups of Formula I or II, selecting a value for n, modifying the remaining R, X, or Y groups, and detecting the capability of one or more of the following: binding to a CyP; inhibition of rotamase activity; in vitro or in vivo neurotrophic, neuroregenerative, or neuroprotectant activity; cell growth promoting activity on neuronal or nervous system cells; or promoting neurite extension.  
     
     
         62 . A cyclophilin binding compound identified by the method of  claim 61 .  
     
     
         63 . The method of  claim 61 , wherein each R of R 4  and R 5  in said compound of Formula II may independently be 
 hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;    where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.    
     
     
         64 . A cyclophilin binding compound identified by the method of  claim 63 .  
     
     
         65 . A compound of the following formula  
       
         
           
           
               
               
           
         
         where n in C n  is 0 or 1;  
         the dashed bond symbol represents an optional bond;  
         X and Y may independently be N, NH, O, S, or a direct bond;  
         R 1  is the same or different from R 2 , and either can be 
 one or more C1-C6 branched or straight chain alkyl or alkenyl groups;  
 one or more C1-C3 branched or straight chain alkyl groups substituted by one or more Q groups;  
 or one or more Q groups, 
 where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof;  
 
 
         and R 3  may be one to three substituents chosen from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, Q as defined above, or a combination thereof;  
         except where R 3  is absent, X and Y are NH, and n is1, then R 1  and R 2  cannot both be benzyl or two phenyl substituents; and  
         except where R 3  is absent, R 1  and R 2  are both benzyl, and n is 0, then X and Y cannot both be NH; and  
         except where R 3  is absent, X and Y are direct bonds, and n is 0, then R 1  and R 2  cannot both be benzyl.  
       
     
     
         66 . A compound of  claim 65 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         67 . A compound  claim 66 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         68 . A compound of  claim 65 , wherein X and Y are N or NH.  
     
     
         69 . A compound of  claim 65 , wherein X and Y are O.  
     
     
         70 . A compound of  claim 65 , wherein n is 0.  
     
     
         71 . A composition comprising a compound of  claim 65  and a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         72 . A compound of the following formula  
       
         
           
           
               
               
           
         
         where n in C n  is 0 or 1;  
         the dashed bond symbol represents an optional bond;  
         X and Y are NH;  
         R 1  is the same or different from R 2 , and either can be 
 one or more C1-C6 branched or straight chain alkyl or alkenyl groups;  
 one or more C1-C3 branched or straight chain alkyl groups substituted by one or more Q groups;  
 or one or more Q groups, 
 where Q, which may or may not be aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof;  
 
 
         and R 3  may be one to three substituents chosen from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, Q as defined above, or a combination thereof;  
         except where n is 0 and R 3  is absent, then R 1  and R 2  cannot both be cyclohexyl or phenyl, or R 1  and R 2  cannot both be two phenyl or two benzyl groups, or R 1  and R 2  both cannot be a monosubstituted phenyl group where the substituent is H, Cl, F, OH, NH 2 , NO 2 , or CH 3  in the para position, or R 1  and R 2  cannot both be 2,4,6 tribromophenyl, or R 1  cannot be cyclohexyl if R 2  is phenyl substituted by a para methyl; and  
         except where n is 0 and R 3  is methyl at the 4 position, then R 1  and R 2  cannot both be phenyl, two benzyl groups, 2-methylcyclohexyl,4-methyl-3-amino-phenyl, para methyl-phenyl, 3-O hydroxyphenol, 2,2,6,6-tetramethyl-4-piperidinyl, 1,2,2,6,6-pentamethyl-4-piperidinyl, or 1,2,4 triazol-3-yl, 3,5,di-tert-butyl-4-hydroxyphenyl, 2-ethylphenyl, 2-chloroethyl, or cyclohexyl; and  
         except where n is 0 and R 3  is two Br groups at the 4 and 6 positions, then R 1  and R 2  cannot both be 2-amidophenyl, 4-dimethylamine-phenyl, or 3- or 4-iodo-phenyl; and  
         except where n is 1 and R 3  is absent, then R 1  and R 2  cannot both be benzyl or benzyl in combination with an additional phenyl or benzyl, or R 1  and R 2  cannot both be a monosubstituted phenyl where the substituent is H, Cl, F, or CH 3  in the para position.  
       
     
     
         73 . A compound of  claim 72 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         74 . A compound of  claim 73 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         75 . A compound of  claim 72 , wherein n is 0.  
     
     
         76 . A composition comprising a compound of  claim 72  and a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         77 . A compound of the following formula  
       
         
           
           
               
               
           
         
         where n in C n  is 0 or 1;  
         the dashed bond symbol represents an optional bond;  
         X and Y are direct bonds;  
         R 1  is the same or different from R 2 , and either can be 
 one or more C1-C6 branched or straight chain alkyl or alkenyl groups;  
 one or more C1-C3 branched or straight chain alkyl groups substituted by one or more Q groups;  
 or one or more Q groups, 
 where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof;  
 
 
         and R 3  may be one to three substituents chosen from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, Q as defined above, or a combination thereof,  
         except where n is 0 and R 3  is absent, then R 1  and R 2  cannot both be a para-substituted benzyl where the para substitution is H, Cl, F, or CH 3 , or R 1  and R 2  cannot both be cyclohexyl; and  
         except where n is 1 and R 3  is absent, then R 1  and R 2  cannot both be a para-substituted benzyl where the para substitution is H, Cl, F, or CH 3 , or where R 3  is up to three substituents from the group H, F, CH 3 , and Br, then R 1  and R 2  cannot be benzyl.  
       
     
     
         78 . A compound of  claim 77 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         79 . A compound of  claim 77 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         80 . A compound of the following formula  
       
         
           
           
               
               
           
         
         where n in C n  is 0 or 1;  
         the dashed bond symbol represents an optional bond;  
         X and Y may independently be N, O, or S;  
         R 1  is the same or different from R 2 , and either can be 
 one or more C1-C6 branched or straight chain alkyl or alkenyl groups;  
 one or more C1-C3 branched or straight chain alkyl groups substituted by one or more Q groups;  
 or one or more Q groups, 
 where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof;  
 
 
         and R 3  may be one to three substituents chosen from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, Q as defined above, or a combination thereof.  
       
     
     
         81 . A compound of  claim 80 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         82 . A compound of  claim 81 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         83 . A compound of the following formula:  
       
         
           
           
               
               
           
         
         where R 4  and R 5  may independently be 
 —N—SO 2 —R,  
 —SO 2 —NRR,  
 —O—R,  
 —CO—N—R,  
 —N—CO—R,  
 —CO—R,  
 
         wherein each R may independently be 
 hydrogen, Q, or a C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO 2 , N, or NH;  
 where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.  
 
       
     
     
         84 . The compound of  claim 83 , wherein each R of R 4  and R 5  may independently be 
 hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;    where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.    
     
     
         85 . A compound of  claim 83 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         86 . A compound of  claim 84 , wherein the compound inhibits cyclophilin rotamase activity with an IC 50  of 1 μM or less.  
     
     
         87 . A compound of  claim 85 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         88 . A compound of  claim 86 , wherein the compound inhibits FKBP rotamase activity with an IC 50  of 10 μM or more.  
     
     
         89 . A compound of  claim 83 , wherein either or both of R 4  and R 5  is N—SO 2 —R.  
     
     
         90 . The compound of  claim 89 , wherein each R of R 4  and R 5  may independently be hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q; where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.  
     
     
         91 . A compound of  claim 83 , wherein either or both of R 4  and R 5  is O—R.  
     
     
         92 . The compound of  claim 91 , wherein each R of R 4  and R 5  may independently be hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q; where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.  
     
     
         93 . A compound of  claim 83 , wherein either or both of R 4  and R 5  is N—CO—R.  
     
     
         94 . The compound of  claim 93 , wherein each R of R 4  and R 5  may independently be hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q; where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.