160233-05-6Relevant articles and documents
A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro
Amano, Masayuki,Koh, Yasuhiro,Das, Debananda,Li, Jianfeng,Leschenko, Sofiya,Wang, Yuan-Fang,Boross, Peter I.,Weber, Irene T.,Ghosh, Arun K.,Mitsuya, Hiroaki
, p. 2143 - 2155 (2007)
We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (P1) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-
Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones
Ali, Akbar,Reddy, G. S. Kiran Kumar,Nalam, Madhavi N. L.,Anjum, Saima Ghafoor,Cao, Hong,Schiffer, Celia A.,Rana, Tariq M.
scheme or table, p. 7699 - 7708 (2010/12/30)
A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds with 2- and 4-substituted phenyloxazolidinones at P2 exhibited lower binding affinities than 3-substituted analogues. Crystal structure analyses of ligand-enzyme complexes revealed different binding modes for 2- and 3-substituted P2 moieties in the protease S2 binding pocket, which may explain their different binding affinities. Several compounds with 3-substituted P2 moieties demonstrated picomolar binding affinity and low nanomolar antiviral potency against patient-derived viruses from HIV-1 clades A, B, and C, and most retained potency against drug-resistant viruses. Further optimization of these compounds using structure-based design may lead to the development of novel protease inhibitors with improved activity against drug-resistant strains of HIV-1.
Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands
Ali, Akbar,Reddy, G. S. Kiran Kumar,Cao, Hong,Anjum, Saima Ghafoor,Nalam, Madhavi N. L.,Schiffer, Celia A.,Rana, Tariq M.
, p. 7342 - 7356 (2007/10/03)
Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2′ phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with Ki values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2′ phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1′ with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor-enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogen-bond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (Ki = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar Ki, which is highly comparable with the best FDA-approved protease inhibitors.
