- Field-based affinity optimization of a novel azabicyclohexane scaffold HIV-1 entry inhibitor
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Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.
- Meuser, Megan E.,Rashad, Adel A.,Ozorowski, Gabriel,Dick, Alexej,Ward, Andrew B.,Cocklin, Simon
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- Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 12. Structure-activity relationships associated with 4-fluoro-6-azaindole derivatives leading to the identification of 1-(4-benzoylpiperazin-1-yl)-2-(4- fluoro-7-[1,2,3]triazol-1-yl-1H-
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A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycl
- Regueiro-Ren, Alicia,Xue, Qiufen M.,Swidorski, Jacob J.,Gong, Yi-Fei,Mathew, Marina,Parker, Dawn D.,Yang, Zheng,Eggers, Betsy,D'Arienzo, Celia,Sun, Yongnian,Malinowski, Jacek,Gao, Qi,Wu, Dedong,Langley, David R.,Colonno, Richard J.,Chien, Caly,Grasela, Dennis M.,Zheng, Ming,Lin, Pin-Fang,Meanwell, Nicholas A.,Kadow, John F.
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p. 1656 - 1669
(2013/04/23)
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- Aminium salts of 1,2,3-triazoles as prodrugs of drugs including antiviral agents
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This disclosure provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the disclosure is concerned with new aminium salts of 1,2,3-triazoles which can be used as prodrugs to improve
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Page/Page column 11; 14
(2008/06/13)
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- Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein
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A process is provided for preparing triazole substituted azaindoleoxoacetic piperazine derivative. Novel intermediates produced in the above process, and novel N-1 and amorphous forms of a 1,2,3-triazole substituted azaindoloxoacetic piperazine derivatives and processes for producing such novel forms are also provided.
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Page/Page column 33
(2008/06/13)
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- Prodrugs of piperazine and substituted piperidine antiviral agents
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This invention provides for prodrug Compounds I, pharmaceutical compositions thereof, and their use in treating HIV infection. wherein: X is C or N with the proviso that when X is N, R1 does not exist; W is C or N with the proviso that when W is N, R2 does not exist; V is C; E is hydrogen or a pharmaceutically acceptable salt thereof; and Y is selected from the group consisting of Also, this invention provides for intermediate Compounds II useful in making prodrug Compounds I. wherein: L and M are independently selected from the group consisting of C1-C6 alkyl, phenyl, benzyl, trialkylsilyl, -2,2,2-trichloroethoxy and 2-trimethylsilylethoxy.
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Page/Page column 32
(2010/02/14)
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- Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with azaindoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.
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- Indole, azaindole and related heterocyclic sulfonylureido piperazine derivatives
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with sulfonylureido piperazine derivatives of Formula I. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS. 1wherein: Z is 2Q is selected from the group consisting of: 3—W— is 4—represents a carbon-carbon bond or does not exist; and A is NR13R14.
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Page/Page column 37
(2010/02/05)
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- INDOLE, AZAINDOLE AND RELATED HETEROCYCLIC UREIDO AND THIOUREIDO PIPERAZINE DERIVATIVES
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with ureido and thioureido piperazine derivatives of Formula (I). These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS. The compounds of Formula (I) are Formula (I) wherein:Y is O or S;Z is Formula (II); Q is selected from the group consisting of Formula (A) and Formula (B); m is 2;A is NRR; and-W- is Formula (C).
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- Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with new piperidine 4-alkenyl derivatives that possess unique antiviral activity. More particularly, the present invention relates to compounds useful for the treatment of HIV and AIDS. The compounds of the invention for the general Formula I: wherein: Z is Q is selected from the group consisting of: —W— is
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Page/Page column 126
(2010/02/06)
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