title: Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.
abstract: The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada. Electronic address: bernard.cote67@videotron.ca.
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Ernest
authors.initials: E
authors.lastname: Asante-Appiah
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Bayly
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Leanne
authors.initials: L
authors.lastname: Bédard
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Blouin
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cauchon
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Chan
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Amandine
authors.initials: A
authors.lastname: Chefson
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Coulombe
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Wanda
authors.initials: W
authors.lastname: Cromlish
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Smita
authors.initials: S
authors.lastname: Debnath
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Deschênes
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Kristina
authors.initials: K
authors.lastname: Dupont-Gaudet
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Forget
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Danny
authors.initials: D
authors.lastname: Gauvreau
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Melina
authors.initials: M
authors.lastname: Girardin
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Guiral
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Langlois
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Rob
authors.initials: R
authors.lastname: Papp
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Plamondon
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Amélie
authors.initials: A
authors.lastname: Roy
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Roy
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Ria
authors.initials: R
authors.lastname: Seliniotakis
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Miguel
authors.initials: M
authors.lastname: St-Onge
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ouellet
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Tawa
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Truchon
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Joe
authors.initials: J
authors.lastname: Vacca
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Wrona
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486-0004, United States.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009154:Mutation; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C000592662:doravirine
keywords: HIV; Inhibitor; Non-nucleoside reverse transcriptase; Pyridone; Triazolinone