Cyclic Peptide Antiviral Agents and Methods Using Same

Abstract

The present invention includes novel cyclic peptides of formula (I). The present invention further includes novel cyclic peptides conjugated with a gold nanoparticle, and methods of using the same. The invention further provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of the invention. The invention further provides a method of treating, reducing, or preventing HIV-1 infection in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of the invention.

1 . A cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof:
   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1   (I),
   
       wherein in (I):
 Xaa 1  is selected from the group consisting of absent, Glu and Arg; 
 Xaa 2  is selected from the group consisting of absent, Gly, Phe, Lys, Asp, Glu, Ile, Arg and Cit; 
 Xaa 3  is selected from the group consisting of absent, Asn, Asp, Ile, Glu, butanedioic acid, and 2-cyclohexylglycine; 
 Xaa 4  is selected from the group consisting of Asn and Asp; 
 Xaa 5  is a modified glycine of formula (III) 
 
       
         
           
           
               
               
           
         
       
       wherein R III  is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl;
 Xaa 6  is the modified proline of formula (IV) 
 
       
         
           
           
               
               
           
         
       
       wherein in (IV):
   R IV  is selected from the group consisting of: adamantyl substituted with 0-2 C 1 -C 6  alkyl groups; —(C 0 -C 4  alkyl) phenyl, wherein the phenyl is substituted with 0-2 C 1 -C 6  alkyl groups; phenyl substituted with R 1  and with 0-2 C 1 -C 6  alkyl groups;   and heteroaryl substituted with R 1  and with 0-2 C 1 -C 6  alkyl groups;
 wherein each occurrence of R 1  is independently selected from the group consisting of phenyl substituted with 0-2 C 1 -C 6  alkyl groups and heteroaryl substituted with 0-2 C 1 -C 6  alkyl groups; and 
 wherein each occurrence of heteroaryl is independently selected from the group consisting of pyridine, pyrimidine, thiophene, furan, pyrrole, imidazole, oxazole, oxadiazole, thiazole, thiadiazolyl, isothiazole, and tetrazole; 
   
 Xaa 7  is selected from the group consisting of Trp and 3-(3-benzothienyl)-L-alanine; 
 Xaa 8  is selected from the group consisting of Ser, Thr, 2,4-diaminobutanoic acid, Orn and Lys; 
 Xaa 9  is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, Glu-Ala, Glu-Ala-Met, Glu-Ala-Met-Met, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid; 
 P 1  is absent, or is a group that comprises at least one thiol group and is covalently linked through an amide bond to (i) the C-terminus of Xaa 9  if Xaa 9  is not absent, or (ii) the C-terminus of Xaa 8  if Xaa 9  is absent; 
 the side chain amino group of one residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9 , Orn at Xaa 9 , and Lys at Xaa 9  forms an amide bond with the side chain carboxylic acid group of one residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3 , succinic acid at Xaa 3 , and Asp at Xaa 4 ; and 
 the C-terminus of Xaa 8  is optionally amidated if Xaa 9  and P 1  are absent, or the C-terminus of Xaa 9  is optionally amidated if P 1  is absent. 
 
     
     
         2 . The cyclic compound of  claim 1 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         ‘NH’ is derived from the side chain amino group of a residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9 , Orn at Xaa 9 , and Lys at Xaa 9 , and 
         ‘C═O’ is derived from the side chain carboxylic acid group of a residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3 , succinic acid at Xaa 3 , and Asp at Xaa 4 . 
       
     
     
         3 . The cyclic compound of  claim 1 , which is the cyclic compound of formula (II):
   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1   (II),
   
       wherein in (II):
 Xaa 3  is selected from the group consisting of Asn, Asp, succinic acid, and Glu; 
 Xaa 4  is Asn; 
 Xaa 5  is Ile; and 
 Xaa 7  is Trp. 
 
     
     
         4 . The compound of  claim 1 , wherein Xaa 5  is selected from the group consisting of Ile, Leu, norleucine (Nle), cyclopropylglycine, cyclobutylglycine, cyclopentylglycine, and cyclohexylglycine. 
     
     
         5 . The compound of  claim 1 , wherein R III  is a secondary or tertiary hydrocarbyl group. 
     
     
         6 . The compound of  claim 5 , wherein R III  is selected from the group consisting of cyclohexyl, —CH(CH 3 )(C 1 -C 4  alkyl), and —C(CH 3 ) 2 (C 1 -C 3  alkyl). 
     
     
         7 . The compound of  claim 1 , wherein one of the following applies: (a) the C-terminus of Xaa 8  is not amidated if Xaa 9  and P 1  are absent, or wherein the C-terminus of Xaa 9  is not amidated if P 1  is absent; (b) the C-terminus of Xaa 8  is amidated if Xaa 9  and P 1  are absent, or wherein the C-terminus of Xaa 9  is amidated if P 1  is absent. 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein, if the carbon alpha to the carboxyl group of Xaa 8  is chiral, the stereochemistry of the alpha carbon is S. 
     
     
         10 . The compound of  claim 1 , wherein in (IV) the heteroaryl is thiophene. 
     
     
         11 . The compound of  claim 1 , wherein R IV  is selected from the group consisting of:
 —(C 0 -C 4  alkyl) phenyl, wherein the phenyl is substituted with 1-2 C 1 -C 6  alkyl groups, wherein one of the C 1 -C 6  alkyl groups is at the para position of the phenyl group;   
       
         
           
           
               
               
           
         
       
       wherein each occurrence of R 1  is independently C 1 -C 6  alkyl; m is 0, 1, or 2; and n is 0 or 1. 
     
     
         12 . The compound of  claim 1 , wherein P 1  is not absent. 
     
     
         13 . The compound of  claim 12 , wherein P 1  comprises at least one cysteine residue. 
     
     
         14 . The compound of  claim 12 , wherein P 1  is selected from the group consisting of
 β Ala Gln β Ala Cys-NH 2 , β Ala Gln β Ala Cys,   NH 2 (CH 2 CH 2 O) 0-10 CH 2 C(═O)NHCH(CH 2 SH)C(═O)OH,   NH 2 (CH 2 CH 2 O) 0-10 CH 2 C(═O)NHCH(CH 2 SH)C(═O)NH 2 ,   NH 2 (CH 2 ) 0-12 CH 2 C(═O)NHCH(CH 2 SH)C(═O)OH,   NH 2 (CH 2 ) 0-12 CH 2 C(═O)NHCH(CH 2 SH)C(═O)NH 2 , and   NH 2 CH 2 CH 2 OCH 2 CH 2 OC(═O)NHCH(CH 2 SH)C(═O)NH 2 .   
     
     
         15 . The compound of  claim 1 , which is selected from the group consisting of:
 29N-2 or 36 [also known as (3S,6S,14S, 17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4, 7,10,13,18]hexaazacyclotricosine-6-carboxamide]   
       
         
           
           
               
               
           
         
         37 [also known as (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide] 
       
       
         
           
           
               
               
           
         
         38 [also known as (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide] 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17 S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-7-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14 S,17 S,20 S,24 S,25 aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17 S,20S,24S,25aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         ((3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1l-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
       
       or a salt or solvate thereof. 
     
     
         16 . The compound of  claim 1 , which is a compound of formula (V): 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  is NH 2  or H; 
 R b  is cyclohexyl or sec-butyl; 
 R c  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         R d  is NH or S; 
       
       or a salt or solvate thereof. 
     
     
         17 . The compound of  claim 1 , wherein P 1  is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of  claim 1 . 
     
     
         20 . The composition of  claim 19 , wherein P 1  in (I) is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         21 - 23 . (canceled) 
     
     
         24 . A method of treating, reducing or preventing HIV-1 infection in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of  claim 1 . 
     
     
         25 - 29 . (canceled) 
     
     
         30 . A method of reducing the risk of HIV-1 infection in a mammal at risk of HIV-1 exposure, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of  claim 1 . 
     
     
         31 - 35 . (canceled) 
     
     
         36 . A method of promoting virolysis of HIV-1, the method comprising contacting the HIV-1 with an effective amount of at least one cyclic compound of  claim 1 , wherein P 1  is not absent. 
     
     
         37 . The method of  claim 36 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         38 . (canceled) 
     
     
         39 . A method of reducing the rate of or preventing entry of HIV-1 into a cell of a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of  claim 1 . 
     
     
         40 - 41 . (canceled) 
     
     
         42 . The method of  claim 39 , wherein P1 is not absent and (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         43 - 44 . (canceled) 
     
     
         45 . A method of preparing a derivatized gold nanoparticle, the method comprising contacting the nanoparticle with at least one cyclic compound of  claim 1  to generate a reaction system; and isolating the derivatized gold nanoparticle from the reaction system.