Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2‑Carbamoylphenyl Piperidine Moiety
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...
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Published in | Journal of medicinal chemistry Vol. 63; no. 18; pp. 10352 - 10379 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
24.09.2020
Amer Chemical Soc |
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Abstract | 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. |
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AbstractList | 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. 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 , 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 , which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with -alkyl- -aryl benzamides to lower the lipophilicity and restrict the -alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential -alkyl- -aryl benzamide. Among these, orally available (3 )-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 ( ) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism. GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic beta-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 pi-pi 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. |
Author | Ookawara, Mitsugi Hitomi, Yuko Moritoh, Yusuke Aida, Jumpei Watanabe, Koji Yoshitomi, Yayoi Takakura, Nobuyuki Maekawa, Tsuyoshi Takami, Kazuaki Miyamoto, Yasufumi Miwatashi, Seiji Hamada, Teruki Hirozane, Yoshihiko Noguchi, Naoyoshi Watanabe, Masanori Furukawa, Hideki Ito, Ryo Hirata, Yasuhiro |
AuthorAffiliation | Takeda Pharmaceutical Company, Ltd SCOHIA PHARMA Inc Research Research Division |
AuthorAffiliation_xml | – name: Research – name: Research Division – name: SCOHIA PHARMA Inc – name: Takeda Pharmaceutical Company, Ltd |
Author_xml | – sequence: 1 givenname: Hideki orcidid: 0000-0002-9894-7264 surname: Furukawa fullname: Furukawa, Hideki email: hideki.furukawa@takeda.com organization: Takeda Pharmaceutical Company, Ltd – sequence: 2 givenname: Yasufumi surname: Miyamoto fullname: Miyamoto, Yasufumi organization: Takeda Pharmaceutical Company, Ltd – sequence: 3 givenname: Yasuhiro surname: Hirata fullname: Hirata, Yasuhiro organization: Takeda Pharmaceutical Company, Ltd – sequence: 4 givenname: Koji surname: Watanabe fullname: Watanabe, Koji organization: SCOHIA PHARMA Inc – sequence: 5 givenname: Yuko surname: Hitomi fullname: Hitomi, Yuko organization: Takeda Pharmaceutical Company, Ltd – sequence: 6 givenname: Yayoi surname: Yoshitomi fullname: Yoshitomi, Yayoi organization: Takeda Pharmaceutical Company, Ltd – sequence: 7 givenname: Jumpei orcidid: 0000-0002-7546-1915 surname: Aida fullname: Aida, Jumpei organization: Takeda Pharmaceutical Company, Ltd – sequence: 8 givenname: Naoyoshi surname: Noguchi fullname: Noguchi, Naoyoshi organization: SCOHIA PHARMA Inc – sequence: 9 givenname: Nobuyuki surname: Takakura fullname: Takakura, Nobuyuki organization: Takeda Pharmaceutical Company, Ltd – sequence: 10 givenname: Kazuaki surname: Takami fullname: Takami, Kazuaki organization: Takeda Pharmaceutical Company, Ltd – sequence: 11 givenname: Seiji surname: Miwatashi fullname: Miwatashi, Seiji organization: Takeda Pharmaceutical Company, Ltd – sequence: 12 givenname: Yoshihiko surname: Hirozane fullname: Hirozane, Yoshihiko organization: Takeda Pharmaceutical Company, Ltd – sequence: 13 givenname: Teruki surname: Hamada fullname: Hamada, Teruki organization: Takeda Pharmaceutical Company, Ltd – sequence: 14 givenname: Ryo surname: Ito fullname: Ito, Ryo organization: Takeda Pharmaceutical Company, Ltd – sequence: 15 givenname: Mitsugi surname: Ookawara fullname: Ookawara, Mitsugi organization: SCOHIA PHARMA Inc – sequence: 16 givenname: Yusuke surname: Moritoh fullname: Moritoh, Yusuke organization: SCOHIA PHARMA Inc – sequence: 17 givenname: Masanori surname: Watanabe fullname: Watanabe, Masanori organization: SCOHIA PHARMA Inc – sequence: 18 givenname: Tsuyoshi surname: Maekawa fullname: Maekawa, Tsuyoshi email: tsuyoshi.maekawa@scohia.com organization: SCOHIA PHARMA Inc |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32900194$$D View this record in MEDLINE/PubMed |
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Keywords | FFA1 POTENT ACID VIVO INSULIN-SECRETION TAK-875 DISCOVERY AMIDES |
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Snippet | GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic β-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and... GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic beta-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and... |
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SubjectTerms | 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 |
Title | Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2‑Carbamoylphenyl Piperidine Moiety |
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