Composition and Method for the Treatment of Diseases Affected by a Peptide Receptor

Abstract

The present invention includes peptidomimetic compound compositions and methods of making and using peptidomimetic compounds to modulate the activity of a peptide receptor for the treatment of one or more of hyperglycemia, insulin resistance, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia or other symptoms that relate to the function of the targeted receptor. The peptidomimetic includes an oligo-benzamide compound having at least three optionally substituted benzamides.

1 . A method for treating diseases related to a peptide hormone receptor in a subject by administering to the subject a tris-benzamide peptidomimetic compound comprising three optionally substituted benzamides and a peptide hormone receptor binding peptide, wherein the tris-benzamide peptidomimetic compound binds to a peptide hormone receptor. 
     
     
         2 . The method of  claim 1 , wherein the peptide hormone receptor comprises a class B G-protein coupled receptor. 
     
     
         3 . The method of  claim 2 , wherein the class B G-protein coupled receptor is selected from a glucagon-like peptide-1 (GLP-1) receptor, glucagon receptor, glucagon-like peptide-2 (GLP-2) receptor, GIP receptor, PTH receptor, CRF receptor, calcitonin receptor, secretin receptor, VIP receptor, PACAP receptor, and GHRH receptor. 
     
     
         4 . The method of  claim 1 , wherein the tris-benzamide peptidomimetic compound comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R1, R2, and R3, independently comprise a H, one or more optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino, alkylamido, carboxylic ester groups, thioethers groups, carboxylic acids, phosphoryl groups, polycyclic aromatic substituted with a OH, NH 2 , SH, F, Cl, Br, I, NHR, NRR′, CN 3 H 4 , a N, a O, a S, a H, or combination thereof; 
         “A” comprises an acetyl, a Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an amino acid analogue, an artificial amino acid, a peptide sequence of between 2 and 30 amino acids that have greater than 50% homology to a portion of the GLP-1 sequence SEQ. ID. NO.:1, and 
         “B” comprises an optionally substituted lower alkyl, an optionally substituted C1-C7 alkyl, an amino acid, an amino acid analogue, an artificial amino acid, or a portion of the GLP-1 sequence SEQ. ID. NO.:1. 
       
     
     
         5 . A method for modifying glucose metabolism in a subject comprising the steps of:
 administering to the subject a tris-benzamide peptidomimetic compound comprising at three optionally substituted benzamides and a peptide hormone receptor binding peptide, wherein administering the tris-benzamide peptidomimetic compound modifies glucose metabolism by modifying one or more of hyperglycemia, insulin resistance, obesity, hyperlipidemia, or hyperlipoproteinemia.   
     
     
         6 . The method of  claim 5 , wherein the optional substitution of the at three optionally substituted benzamides comprise an optionally substituted group selected from an alkyl, a lower alkyl, an alkoxy, an alkoxyalkyl, a hydroxy, a hydroxyalkyl, an alkenyl, an amino, an imino, a nitrate, an alkylamino, a dialkylamino, a nitro, a nitroso, an aryl, a biaryl, a polycyclic aromatic, an alkylaryl, an arylalkyl, an arylalkoxy, an arylalkylamino, a cycloalkyl, a bridged cycloalkyl, a cycloalkoxy, a cycloalkyl-alkyl, an arylthio, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, an arylsulfonyl, an arylsulfinyl, a caboxamido, a carbamoyl, a carboxyl, a carbonyl, an alkoxycarbonyl, a halogen, a haloalkyl, a haloalkoxy, a heteroayl, a heterocyclic ring, an arylheterocyclic ring, a heterocyclic compounds, an amido, an imido, a guanidino, an alkylamido, a carboxylic ester, a thioether, a carboxylic acid, a phosphoryl group, polycyclic aromatic substituted with a OH, NH 2 , SH, F, Cl, Br, I, NHR, NRR′, CN 3 H 4 , a N, a O, a S, a H, and a combination thereof. 
     
     
         7 . The method of  claim 5 , wherein the tris-benzamide peptidomimetic compound comprises the formula: 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4 and R5 individually comprise a C, a N, a O, a S, a H, one or more optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino, alkylamido, carboxylic ester groups, thioethers groups, carboxylic acids, phosphoryl groups or combination thereof; an acetyl, Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an amino acid analogue, an artificial amino acid, a peptide sequence of between 2 and 30 amino acids that have greater than 50% homology to a portion of the GLP-1 sequence SEQ. ID. NO.:1. 
       
     
     
         8 . The method of  claim 7 , wherein R1, R2, R3, and R4 may individually comprise a H, an acetyl group or a t-butoxycarbonyl group, a Fmoc group, a Cbz group, an Aloc group, a benzyl group, a methyl group, a substituted benzyl group, a 4-fluorobenzyl group or a 2-naphthylmethyl group. 
     
     
         9 . A method for treating a subject that would medically benefit from either stimulation or inhibition of a peptide hormone receptor comprising the steps of:
 administering to the subject a tris-benzamide peptidomimetic compound that functions as an agonist, an antagonist, an inverse agonist or a combination thereof, wherein the tris-benzamide peptidomimetic compound comprises three optionally substituted benzamides and a peptide hormone receptor binding peptide, wherein each of the three optionally substituted benzamides are optionally substituted on a benzene ring with one substitution, wherein each of the substitutions individually comprise one or more optionally substituted groups selected from an alkyl, a lower alkyl, an alkoxy, an alkoxyalkyl, a hydroxy, a hydroxyalkyl, an alkenyl, an amino, an imino, a nitrate, an alkylamino, a dialkylamino, a nitro, a nitroso, an aryl, a biaryl, a polycyclic aromatic, an alkylaryl, an arylalkyl, an arylalkoxy, an arylalkylamino, a cycloalkyl, a bridged cycloalkyl, a cycloalkoxy, a cycloalkyl-alkyl, an arylthio, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, an arylsulfonyl, an arylsulfinyl, a caboxamido, a carbamoyl, a carboxyl, a carbonyl, an alkoxycarbonyl, a halogen, a haloalkyl, a haloalkoxy, a heteroayl, a heterocyclic ring, an arylheterocyclic ring, a heterocyclic compounds, an amido, an imido, a guanidino, an alkylamido, a carboxylic ester, a thioether, a carboxylic acid, a phosphoryl group, polycyclic aromatic substituted with a OH, NH 2 , SH, F, Cl, Br, I, NHR, NRR′, CN 3 H 4 , a N, a O, a S, a H, or a combination thereof.   
     
     
         10 . The method of  claims 9 , wherein one of the one or more substitutions correspond to an i position, one of the one or more substitutions correspond to an i+3 position or an i+4 position, and one of the one or more substitutions correspond to an i+7 position of an α-helix. 
     
     
         11 . The method of  claim 9 , wherein the pharmaceutical peptidomimetic compound is adapted for oral, dermatological, transdermal or parenteral administration. 
     
     
         12 . The method of  claim 9 , further comprising one or more of diluents excipients, active agents, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, aromatic substances, penetration enhancers, surfactants, fatty acids, bile salts, chelating agents, colloids and combinations thereof. 
     
     
         13 . A tris-benzamide peptidomimetic composition that binds to a class B G-protein coupled receptor comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4 and R5 individually comprise a C, a N, a O, a S, a H, one or more optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino, alkylamido, carboxylic ester groups, thioethers groups, carboxylic acids, phosphoryl groups or combination thereof an acetyl, Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an amino acid analogue, an artificial amino acid, a peptide sequence of between 2 and 30 amino acids that have greater than 50% homology to a portion of the GLP-1 sequence SEQ. ID. NO.:1; and 
         wherein at least one group selected from R1, R2, R3, R4 and R5 comprise at least a portion of a class B G-protein coupled receptor protein. 
       
     
     
         14 . The tris-benzamide peptidomimetic composition of  claim 13 , wherein the at least a portion of a class B G-protein coupled receptor comprises at least a portion of a GLP-1 sequence SEQ. ID. NO.:1. 
     
     
         15 . The tris-benzamide peptidomimetic composition of  claim 13 , wherein R1 comprises an acetyl group, R2 comprises a benzyl group, R3 and R4 comprise 4-fluorobenzyl groups, and R5 comprises a peptide chain corresponding to GLP-1(22-36) amide. 
     
     
         16 . The tris-benzamide peptidomimetic composition of  claim 13 , wherein R1 comprises a t-butoxycarbonyl group, R2 comprises a methyl group, R3 comprises a benzyl group, R4 comprises a 2-naphthylmethyl group, and R5 comprises a peptide chain corresponding to GLP-1(22-36) amide. 
     
     
         17 . The tris-benzamide peptidomimetic composition of  claim 13 , wherein R1 comprises a dipeptide (His-Gly), R2 comprises a benzyl group, R3 comprises an isopropyl, and R4 comprises a 4-fluorobenzyl group, and R5 comprises a peptide chain corresponding to GLP-1(22-36) amide. 
     
     
         18 . The tris-benzamide peptidomimetic composition of  claim 13 , wherein R1 comprises a histidine, R2 comprises a benzyl group, R3 comprises an isopropyl, and R4 comprises a 4-fluorobenzyl group, and R5 comprises a peptide chain corresponding to GLP-1(22-36) amide. 
     
     
         19 . The tris-benzamide peptidomimetic composition of  claim 13 , wherein R1 comprises an acetyl group, R2 comprises a benzyl group, R3 comprises an isopropyl group, R4 comprises 4-fluorobenzyl group, and R5 comprises a peptide chain corresponding to GLP-1(22-36) amide. 
     
     
         20 . The tris-benzamide peptidomimetic composition of  claim 13 , wherein R1, R2, R3, and R4 may individually comprise a H, an acetyl group or a t-butoxycarbonyl group, a Fmoc group, a Cbz group, an Aloc group, a benzyl group, a methyl group, a substituted benzyl group, a 4-fluorobenzyl group or a 2-naphthylmethyl group. 
     
     
         21 . A compound comprising the formula: 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4 R5, R6, R7, R8, and R9 individually comprise a C, a N, a O, a S, a H, optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, urea groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino, hydrazido, aminoxy, alkoxyamino, alkylamido, carboxylic ester groups, thioethers groups, carboxylic acids, phosphoryl groups, polycyclic aromatic, substituted polycyclic aromatic, an acetyl, Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an amino acid analogue, an artificial amino acid, a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide a linker of 1-30 amino acids, a linker of an optionally substituted lower alkyl, a linker of an optionally substituted C1-C7 alkyl, a polycyclic aromatic substituted with a OH, a NH 2 , a SH, a F, a Cl, a Br, a I, a NHR, a NRR′, a CN 3 H 4 , a N, a O, a S, a H, a linker of 1-30 amino acids, an optionally substituted C1-C7 alkyl, an optionally substituted linker as seen below 
       
       
         
           
           
               
               
           
         
         wherein X and Y independently comprises a N, a O, a C, a S, or a H and wherein at least one group selected from R1, R2, R3, R4, R5, R6, R7, R8, and R9 comprise at least a portion of a class B G-protein coupled receptor protein.