- Design, synthesis and biological evaluation of protease inhibitors containing morpholine cores with remarkable potency against both HIV-1 subtypes B and C
-
By following up on the design vector of optimizing amine-based HIV-1 protease inhibitors, we have designed and biologically evaluated a novel class of inhibitors with the free nitrogen or sulphone in morpholine cores as P2 ligands in combination with diverse substituted phenylsulfonamide P2′ ligands. As it turns out, a majority of these inhibitors exhibit prominent enzymatic inhibitory activity in low nanomolar ranges with relatively low cytotoxicity. Particularly, inhibitor 1e containing a morpholine carboxamide P2 ligand and a 4-hydroxyphenylsulfonamide P2′ ligand illustrates a robust enzyme inhibitory IC50 value of 90 pM. Furthermore, 1e demonstrates impressive in vivo antiviral activity with EC50 value of 89 nM and a degree of inhibitory potency against the DRV-resistant variant. More importantly, 1e exhibits remarkable activity with EC50 values of 13.59 nM and 8.23 nM against subtype C HIV-1 strains ZM246 and Indie, respectively. Furthermore, the in silico studies provide molecular insights into binding features of inhibitors with HIV-1 protease, and furnish a valuable forecast on further process.
- Cen, Shan,Ding, Jiwei,Dong, Biao,Ma, Ling,Shan, Qi,Wang, Juxian,Wang, Minghua,Wang, Yucheng,Zhang, Guoning,Zhou, Huiyu,Zhou, Jinming,Zhu, Mei
-
-
- Biphenyl/diphenyl ether renin inhibitors: Filling the S1 pocket of renin via the S3 pocket
-
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the p
- Yuan, Jing,Simpson, Robert D.,Zhao, Wei,Tice, Colin M.,Xu, Zhenrong,Cacatian, Salvacion,Jia, Lanqi,Flaherty, Patrick T.,Guo, Joan,Ishchenko, Alexey,Wu, Zhongren,McKeever, Brian M.,Scott, Boyd B.,Bukhtiyarov, Yuri,Berbaum, Jennifer,Panemangalore, Reshma,Bentley, Ross,Doe, Christopher P.,Harrison, Richard K.,McGeehan, Gerard M.,Singh, Suresh B.,Dillard, Lawrence W.,Baldwin, John J.,Claremon, David A.
-
p. 4836 - 4843
(2011/09/16)
-
- RENIN INHIBITORS
-
Disclosed are aspartic protease inhibitors represented by the following structural formula: and pharmaceutically acceptable salts thereof. These compounds are orally active and bind to aspartic proteases to inhibit their activity. They are useful in the t
- -
-
Page/Page column 30-31
(2010/08/07)
-
- Renin Inhibitors
-
Disclosed are compounds having the formula (I): wherein the R1, R2, R3, X, Y, A, L, and G are defined herein. These compounds bind to aspartic proteases to inhibit their activity and are useful in the treatment or amelioration of diseases associated with aspartic protease activity. Also disclosed are methods of use of the compounds of Formula I for ameliorating or treating aspartic protease related disorders in a subject in need thereof.
- -
-
Page/Page column 51
(2010/12/29)
-
- RENIN INHIBITORS
-
Described are compounds which bind to aspartic proteases to inhibit their activity. They are useful in the treatment or amelioration of diseases associated with aspartic protease activity. Also described are methods of use of the compounds described herein in ameliorating or treating aspartic protease related disorders in a subject in need thereof.
- -
-
-
- RENIN INHIBITORS
-
Disclosed are compounds of Formula (I) wherein the R, R1, R2, R3, X, Y, A, Q, E, and G are defined herein. These compounds bind to aspartic proteases to inhibit their activity and are useful in the treatment or amelioration of diseases associated with aspartic protease activity. Also disclosed are methods of use of the compounds of Formula I for ameliorating or treating aspartic protease related disorders in a subject in need thereof.
- -
-
Page/Page column 112; 114
(2008/12/04)
-
- PIPERIDINE AND MORPHOLINE RENIN INHIBITORS
-
Described are compounds which are orally active and bind to renin to inhibit its activity. They are useful in the treatment or amelioration of diseases associated with renin activity. Also described are methods of use of these compounds for treating or ameliorating a renin mediated disorder in a subject.
- -
-
-
- DIAMINOPROPANOL RENIN INHIBITORS
-
Described are diaminopropanols of which are orally active and bind to renin to inhibit its activity. They are useful in the treatment or amelioration of diseases associated with elevated levels of renin activity or in the treatment of aspartic protease me
- -
-
-
- ASPARTIC PROTEASE INHIBITORS
-
The present invention is directed to aspartic protease inhibitors. Certain aspartic protease inhibitors of the invention can be represented by the following structural formula or a pharmaceutically acceptable salt thereof. The present invention is also directed to pharmaceutical compositions comprising the disclosed aspartic protease inhibitors. The present invention is further directed to methods of antagonizing one or more aspartic proteases in a subject in need thereof, and methods for treating an aspartic protease mediated disorder in a subject using the disclosed aspartic protease inhibitors.
- -
-
Page/Page column 176-177
(2010/11/27)
-
- MORPHOLINE CARBOXAMIDE PROKINETICIN RECEPTOR ANTAGONISTS
-
The present invention is directed to morpholine carboxamide compounds which are antagonists of prokineticin receptors, in particular antagonists of prokineticin 2 receptors, and which are useful in the treatment or prevention of neurological and psychiatr
- -
-
Page/Page column 28-29
(2008/06/13)
-
