title: Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.
abstract: HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States. Electronic address: john_schreier@merck.com.
authors.forename: John D
authors.initials: JD
authors.lastname: Schreier
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Embrey
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Izzat T
authors.initials: IT
authors.lastname: Raheem
authors.affiliation: Merck Frost Centre for Therapeutic Research, Kirkland, QC, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Barbe
authors.affiliation: Discovery Process Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.affiliation: Discovery Pharmaceutical Sciences, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: David
authors.initials: D
authors.lastname: Dubost
authors.affiliation: Discovery Process Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Jamie
authors.initials: J
authors.lastname: McCabe Dunn
authors.affiliation: Infectious Disease Biology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Jay
authors.initials: J
authors.lastname: Grobler
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hartingh
authors.affiliation: Infectious Disease Biology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Klein
authors.affiliation: Infectious Disease Biology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Moore
authors.affiliation: Merck Frost Centre for Therapeutic Research, Kirkland, QC, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Natasa
authors.initials: N
authors.lastname: Pajkovic
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States; Merck Frost Centre for Therapeutic Research, Kirkland, QC, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Powell
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rada
authors.affiliation: Global Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sisko
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Steele
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: John
authors.initials: J
authors.lastname: Wai
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Abbas
authors.initials: A
authors.lastname: Walji
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D004285:Dogs; D015658:HIV Infections / Q000188:drug therapy; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D011728:Pyridones; C017679:2-hydroxypyridine; D019427:HIV Integrase
keywords: 2-pyridinone aminal; HIV Integrase; Structure activity relationship