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Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2‑Carbamoylphenyl Piperidine Moiety
journal contribution
posted on 2020-09-09, 08:43 authored by Hideki Furukawa, Yasufumi Miyamoto, Yasuhiro Hirata, Koji Watanabe, Yuko Hitomi, Yayoi Yoshitomi, Jumpei Aida, Naoyoshi Noguchi, Nobuyuki Takakura, Kazuaki Takami, Seiji Miwatashi, Yoshihiko Hirozane, Teruki Hamada, Ryo Ito, Mitsugi Ookawara, Yusuke Moritoh, Masanori Watanabe, Tsuyoshi MaekawaGPR40/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.
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terminal aryl ringreported biaryl derivativemethoxyphenyl ) piperidindimethylpropyl )( 6coupled receptor expressedcentral aryl ringameliorated glucose tolerance>- aryl benzamides>- aryl benzamide>- alkyl moieties>- alkyl -<pivotal regulatorspancreatic βorally availableimproved potencyhydrophobic moietyglycemic controlattractive target1 release
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