title: Diphenyl ether non-nucleoside reverse transcriptase inhibitors with excellent potency against resistant mutant viruses and promising pharmacokinetic properties.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. zachary.sweeney@roche.com
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Kennedy-Smith
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wu
authors.forename: Nidhi
authors.initials: N
authors.lastname: Arora
authors.forename: J Roland
authors.initials: JR
authors.lastname: Billedeau
authors.forename: James P
authors.initials: JP
authors.lastname: Davidson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fretland
authors.forename: Julie Q
authors.initials: JQ
authors.lastname: Hang
authors.forename: Gabrielle M
authors.initials: GM
authors.lastname: Heilek
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Donald
authors.initials: D
authors.lastname: Hirschfeld
authors.forename: Petra
authors.initials: P
authors.lastname: Inbar
authors.forename: Hassan
authors.initials: H
authors.lastname: Javanbakht
authors.forename: Jesper A
authors.initials: JA
authors.lastname: Jernelius
authors.forename: Qingwu
authors.initials: Q
authors.lastname: Jin
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Weiling
authors.initials: W
authors.lastname: Liang
authors.forename: Ralf
authors.initials: R
authors.lastname: Roetz
authors.forename: Keshab
authors.initials: K
authors.lastname: Sarma
authors.forename: Mark
authors.initials: M
authors.lastname: Smith
authors.forename: Dimitrio
authors.initials: D
authors.lastname: Stefanidis
authors.forename: Guoping
authors.initials: G
authors.lastname: Su
authors.forename: Judy M
authors.initials: JM
authors.lastname: Suh
authors.forename: Armando G
authors.initials: AG
authors.lastname: Villaseñor
authors.forename: Michael
authors.initials: M
authors.lastname: Welch
authors.forename: Fang-Jie
authors.initials: FJ
authors.lastname: Zhang
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
mesh_terms: 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
chemical_list: D019380:Anti-HIV Agents; D010647:Phenyl Ethers; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase