Discovery of novel 5-oxa-2,6-diazaspiro[3.4]oct-6-ene derivatives as potent, selective, and orally available somatostatin receptor subtype 5 (SSTR5) antagonists for treatment of type 2 diabetes mellitus

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 15; pp. 4175 - 4193
• Main Authors: Hirose, Hideki, Yamasaki, Takeshi, Ogino, Masaki, Mizojiri, Ryo, Tamura-Okano, Yumiko, Yashiro, Hiroaki, Muraki, Yo, Nakano, Yoshihide, Sugama, Jun, Hata, Akito, Iwasaki, Shinji, Watanabe, Masanori, Maekawa, Tsuyoshi, Kasai, Shizuo
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2017; Elsevier
• Subjects: Animals; Anti-diabetic drug; Biochemistry & Molecular Biology; Carbon-13 Magnetic Resonance Spectroscopy; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2 - drug therapy; Drug Discovery; hERG inhibition; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; OGTT; Pharmacology & Pharmacy; Physical Sciences; Proton Magnetic Resonance Spectroscopy; Receptors, Somatostatin - antagonists & inhibitors; Science & Technology; Somatostatin; SSTR5; SSTR5 antagonist; LiAlH4; SAR; HBA; HFD; HLM; DM; HBD; CHO; MLM; P(nBu)3; Fsp3; MS4A; HOBt; SSTR5 antagonist; Somatostatin; hERG; Anti-diabetic drug; KO; WSC; hERG inhibition; Et3N; SSTR5; ADDP; OGTT; NCS; SMALL-MOLECULE; MECHANISMS; SECRETION; GLUCAGON
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.06.007

[Display omitted] Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity. A subsequent optimization study revealed that replacement of the 4-benzoic acid with an isonipecotic acid dramatically reduced hERG inhibition (5.6% inhibition at 30μM) by eliminating π-related interaction with hERG K+ channel, which resulted in the identification of 1-(2-((2,6-diethoxy-4′-fluorobiphenyl-4-yl)methyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)piperidin-4-carboxylic acid 25a (hSSTR5/mSSTR5 IC50=9.6/57nM). Oral administration of 25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration.