Design, Synthesis, and Preclinical Profiling of GSK3739936 (BMS-986180), an Allosteric Inhibitor of HIV-1 Integrase with Broad-Spectrum Activity toward 124/125 Polymorphs.

Autor:	Naidu BN; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Patel M; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., McAuliffe B; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Ding B; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Cianci C; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543, United States., Simmermacher J; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Jenkins S; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Parker DD; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Sivaprakasam P; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543, United States., Khan JA; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543, United States., Kish K; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543, United States., Lewis H; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543, United States., Hanumegowda U; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Krystal M; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States., Meanwell NA; Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey 08543, United States., Kadow JF; ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Mar 24; Vol. 65 (6), pp. 4949-4971. Date of Electronic Publication: 2022 Mar 02.
DOI:	10.1021/acs.jmedchem.1c02169
Abstrakt:	Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29 .
Databáze:	MEDLINE
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