Diphenyl ether non-nucleoside reverse transcriptase inhibitors with excellent potency against resistant mutant viruses and promising pharmacokinetic properties.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are part of the preferred treatment regimens for individuals infected with HIV. These NNRTI-based regimens are efficacious, but the most popular NNRTIs have a low genetic barrier to resistance and have been associated with adverse events. There is therefore still a need for efficacious antiviral medicines that facilitate patient adherence and allow durable suppression of viral replication. As part of an extensive program targeted toward the discovery of NNRTIs that have favorable pharmacokinetic properties, good potency against NNRTI-resistant viruses, and a high genetic barrier to drug resistance, we focused on the optimization of a series of diaryl ether NNRTIs. In the course of this effort, we employed molecular modeling to design a new set of NNRTIs that that are active against wild-type HIV and key NNRTI-resistant mutant viruses. The structure-activity relationships observed in this series of compounds provide insight into the structural features required for NNRTIs that inhibit the replication of a wide range of mutant viruses. Selected compounds have promising pharmacokinetic profiles.
Sweeney
Zachary K
ZK
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. zachary.sweeney@roche.com
Kennedy-Smith
Joshua J
JJ
Wu
Jeffrey
J
Arora
Nidhi
N
Billedeau
J Roland
JR
Davidson
James P
JP
Fretland
Jennifer
J
Hang
Julie Q
JQ
Heilek
Gabrielle M
GM
Harris
Seth F
SF
Hirschfeld
Donald
D
Inbar
Petra
P
Javanbakht
Hassan
H
Jernelius
Jesper A
JA
Jin
Qingwu
Q
Li
Yu
Y
Liang
Weiling
W
Roetz
Ralf
R
Sarma
Keshab
K
Smith
Mark
M
Stefanidis
Dimitrio
D
Su
Guoping
G
Suh
Judy M
JM
Villaseñor
Armando G
AG
Welch
Michael
M
Zhang
Fang-Jie
FJ
Klumpp
Klaus
K
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D003198:Computer Simulation; D004285:Dogs; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics; D006678:HIV / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009154:Mutation; D010647:Phenyl Ethers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D010647:Phenyl Ethers; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase