Premium
Bicyclic Hydroxy‐1 H ‐pyrrolopyridine‐trione Containing HIV‐1 Integrase Inhibitors
Author(s) -
Zhao Xue Zhi,
Maddali Kasthuraiah,
Metifiot Mathieu,
Smith Steven J.,
Vu B. Christie,
Marchand Christophe,
Hughes Stephen H.,
Pommier Yves,
Burke Terrence R.
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01270.x
Subject(s) - raltegravir , integrase , integrase inhibitor , chemistry , mutant , potency , elvitegravir , bicyclic molecule , stereochemistry , in vitro , human immunodeficiency virus (hiv) , pharmacology , biochemistry , biology , virology , antiretroviral therapy , gene , viral load
HIV‐1 integrase (IN) is a validated therapeutic target for the treatment of AIDS. However, the emergence of resistance to raltegravir, the sole marketed FDA‐approved IN inhibitor, emphasizes the need to develop second‐generation inhibitors that retain efficacy against clinically relevant IN mutants. We report herein bicyclic hydroxy‐1 H ‐pyrrolopyridine‐triones as a new family of HIV‐1 integrase inhibitors that were efficiently prepared using a key ‘Pummerer cyclization deprotonation cycloaddition’ cascade of imidosulfoxides. In in vitro HIV‐1 integrase assays, the analogs showed low micromolar inhibitory potencies with selectivity for strand transfer reactions as compared with 3′‐processing inhibition. A representative inhibitor ( 5e ) retained most of its inhibitory potency against the three major raltegravir‐resistant IN mutant enzymes, G140S/Q148H, Y143R, and N155H. In antiviral assays employing viral vectors coding these IN mutants, compound 5e was approximately 200‐ and 20‐fold less affected than raltegravir against the G140S/Q148H and Y143R mutations, respectively. Against the N155H mutation, 5e was approximately 10‐fold less affected than raltegravir. Thus, our new compounds represent a novel structural class that may be further developed to overcome resistance to raltegravir, particularly in the case of the G140S/Q148H mutations.