Optimization of physicochemical properties of pyrrolidine GPR40 AgoPAMs results in a differentiated profile with improved pharmacokinetics and reduced off-target activities.

Autor:	Jurica EA; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States. Electronic address: Elizabeth.Jurica@bms.com., Wu X; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Williams KN; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Haque LE; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Rampulla RA; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Mathur A; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Zhou M; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Cao G; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Cai H; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Wang T; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Liu H; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Xu C; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Kunselman LK; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Antrilli TM; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Hicks MB; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Sun Q; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Dierks EA; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Apedo A; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Moore DB; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Foster KA; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Cvijic ME; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Panemangalore R; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Khandelwal P; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Wilkes JJ; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Zinker BA; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Robertson DG; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Janovitz EB; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Galella M; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Li YX; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Li J; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Ramar T; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Jalagam PR; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Jayaram R; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Whaley JM; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Barrish JC; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Robl JA; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Ewing WR; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States., Ellsworth BA; Research and Development, Bristol Myers Squibb, Co., P.O. Box 4000, Princeton, NJ 08543-4000, United States.
Jazyk:	angličtina
Zdroj:	Bioorganic & medicinal chemistry [Bioorg Med Chem] 2023 May 01; Vol. 85, pp. 117273. Date of Electronic Publication: 2023 Apr 04.
DOI:	10.1016/j.bmc.2023.117273
Abstrakt:	GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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