Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2‑Carbamoylphenyl Piperidine Moiety

• Published in: Journal of medicinal chemistry Vol. 63; no. 18; pp. 10352 - 10379
• Main Authors: Furukawa, Hideki, Miyamoto, Yasufumi, Hirata, Yasuhiro, Watanabe, Koji, Hitomi, Yuko, Yoshitomi, Yayoi, Aida, Jumpei, Noguchi, Naoyoshi, Takakura, Nobuyuki, Takami, Kazuaki, Miwatashi, Seiji, Hirozane, Yoshihiko, Hamada, Teruki, Ito, Ryo, Ookawara, Mitsugi, Moritoh, Yusuke, Watanabe, Masanori, Maekawa, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.09.2020; Amer Chemical Soc
• Subjects: Animals; Benzamides - chemical synthesis; Benzamides - pharmacokinetics; Benzamides - therapeutic use; Chemistry, Medicinal; CHO Cells; Cricetulus; Diabetes Mellitus, Experimental - drug therapy; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Life Sciences & Biomedicine; Male; Mice, Inbred ICR; Molecular Structure; Pharmacology & Pharmacy; Piperidines - chemical synthesis; Piperidines - pharmacokinetics; Piperidines - therapeutic use; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - agonists; Science & Technology; Structure-Activity Relationship; FFA1; POTENT; ACID; VIVO; INSULIN-SECRETION; TAK-875; DISCOVERY; AMIDES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00843

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic β-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)­phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π–π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)­(6-methylpyridin-2-yl)­carbamoyl)-5-methoxyphenyl)­piperidin-4-yl)­methoxy)­pyridin-4-yl)­propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.