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. Issue 15 (1st August 2017)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 15(2017)
• Page Start: 4175
• Page End: 4193
• Publication Date: 2017-08-01
• Subjects: SSTR5 somatostatin receptor subtype 5 -- OGTT oral glucose tolerance test -- hERG human ether-a-go-go related gene -- DM diabetes mellitus -- HFD high-fat diet -- NCS N-chlorosuccinimide -- WSC 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride -- HOBt 1-hydroxybenzotriazole -- Et3N triethylamine -- MS4A molecular sieve 4A -- LiAlH4 lithium aluminium hydride -- ADDP 1, 1′-(azodicarbonyl)dipiperidine -- P(nBu)3 tributylphosphine -- SAR structureactivity relationship -- HBA hydrogen bond acceptor -- HBD hydrogen bond donor -- Fsp3 fraction of sp3 carbons -- CHO Chinese hamster ovary -- HLM human liver microsome -- MLM mouse liver microsome -- KO knock out; Somatostatin -- SSTR5 -- SSTR5 antagonist -- Anti-diabetic drug -- hERG inhibition -- OGTT; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.06.007
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N -benzyl azetidine derivatives1 and2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of1 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 derivative10c 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 30 μM) 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 acid25a (hSSTR5/mSSTR5 IC50 = 9.6/57 nM). Oral administration of25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration.