Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold.

Autor:	Gillis EP; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Parcella K; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Bowsher M; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Cook JH; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Iwuagwu C; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Naidu BN; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Patel M; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Peese K; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Huang H; Discovery Biology, ViiV Healthcare, Branford, Connecticut 06405, United States., Valera L; Discovery Biology, ViiV Healthcare, Branford, Connecticut 06405, United States., Wang C; Discovery Biology, ViiV Healthcare, Branford, Connecticut 06405, United States., Kieltyka K; Discovery Pharmaceutics, DMPK and Toxicology, ViiV Healthcare, Branford, Connecticut 06405, United States., Parker DD; Discovery Pharmaceutics, DMPK and Toxicology, ViiV Healthcare, Branford, Connecticut 06405, United States., Simmermacher J; Discovery Pharmaceutics, DMPK and Toxicology, ViiV Healthcare, Branford, Connecticut 06405, United States., Arnoult E; Molecular Design, GSK, Collegeville, Pennsylvania 19426, United States., Nolte RT; Protein Cellular and Structural Sciences, GSK, Collegeville, Pennsylvania 19426, United States., Wang L; Protein Cellular and Structural Sciences, GSK, Collegeville, Pennsylvania 19426, United States., Bender JA; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey 08543, United States., Frennesson DB; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Cambridge, Massachusetts 02142, United States., Saulnier M; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey 08543, United States., Wang AX; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey 08543, United States., Meanwell NA; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey 08543, United States., Belema M; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey 08543, United States., Hanumegowda U; Discovery Pharmaceutics, DMPK and Toxicology, ViiV Healthcare, Branford, Connecticut 06405, United States.; ViiV Discovery, ViiV Healthcare, Branford, Connecticut 06405, United States., Jenkins S; Discovery Pharmaceutics, DMPK and Toxicology, ViiV Healthcare, Branford, Connecticut 06405, United States., Krystal M; Discovery Biology, ViiV Healthcare, Branford, Connecticut 06405, United States., Kadow JF; Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States., Cockett M; ViiV Discovery, ViiV Healthcare, Branford, Connecticut 06405, United States., Fridell R; Discovery Biology, ViiV Healthcare, Branford, Connecticut 06405, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Feb 09; Vol. 66 (3), pp. 1941-1954. Date of Electronic Publication: 2023 Jan 31.
DOI:	10.1021/acs.jmedchem.2c01732
Abstrakt:	Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro , are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.
Databáze:	MEDLINE
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