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  3. Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists

Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists

  • Bioorg Med Chem Lett. 2017 Dec 1;27(23):5213-5220. doi: 10.1016/j.bmcl.2017.10.046.
Hyojin Kim 1,  Suk Joon Cho 2,  Minjin Yoo 3,  Seung Kyu Kang 4,  Kwang Rok Kim 4,  Hwan Hee Lee 4,  Jin Sook Song 4,  Sang Dal Rhee 4,  Won Hoon Jung 4,  Jin Hee Ahn 5,  Jae-Kyung Jung 2,  Kwan-Young Jung 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
  • 2 College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea.
  • 3 Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea.
  • 4 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 5 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 6 Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: krjeong@krict.re.kr.
PMID: 29103971 DOI: 10.1016/j.bmcl.2017.10.046
Abstract

A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.

Keywords

4-(Phenoxymethyl)thiazole; GPR119 agonists; OGTT; Pyrrolidine-2,5-dione; Type 2 diabetes.

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