2. Academic Validation
  3. Discovery of novel 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives as orally bioavailable TRPV4 antagonists for the treatment of pain: Part 1

Discovery of novel 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives as orally bioavailable TRPV4 antagonists for the treatment of pain: Part 1

  • Bioorg Med Chem Lett. 2016 Oct 15;26(20):4930-4935. doi: 10.1016/j.bmcl.2016.09.013.
Naoki Tsuno 1,  Akira Yukimasa 2,  Osamu Yoshida 2,  Yusuke Ichihashi 2,  Takatsugu Inoue 2,  Tatsuhiko Ueno 2,  Hiroki Yamaguchi 2,  Hidetoshi Matsuda 3,  Satoko Funaki 4,  Natsue Yamanada 2,  Miki Tanimura 2,  Daiki Nagamatsu 4,  Yoko Nishimura 4,  Tetsuji Ito 4,  Masahiko Soga 2,  Narumi Horita 3,  Miyuki Yamamoto 2,  Mikie Hinata 2,  Masayuki Imai 5,  Yasuhide Morioka 2,  Toshiyuki Kanemasa 2,  Gaku Sakaguchi 5,  Yasuyoshi Iso 2
Affiliations

Affiliations

  • 1 Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan. Electronic address: naoki.tsuno@shionogi.co.jp.
  • 2 Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan.
  • 3 Shionogi Techno Advance Research Co., Ltd., Japan.
  • 4 Research Laboratory for Development, Shionogi & Co., Ltd., Japan.
  • 5 Pharmaceutical Research Division, Shionogi & Co., Ltd., Japan.
PMID: 27637151 DOI: 10.1016/j.bmcl.2016.09.013
Abstract

A novel series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives were found by high throughput screening of the TRPV4 receptor, at which these compounds showed competitive antagonist potential against 4α-phorbol 12,13-didecanoate (4αPDD) as the selective TRPV4 agonist and showed excellent selectivity for TRPV1, N-type and L-type calcium ion channels, but poor ADME profile. In our SAR strategy, we found that the lead molecule 1 also having the unique 3-oxa-9-azabicyclo [3.3.1] nonan-7-one on the right part showed potent TRPV4 antagonist activity, good solubility at pH 6.8, good microsomal stability for human and better ADME profile including oral bioavailability. Moreover, compound 1 had an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig. In this letter, we report a lead optimization process to identify the lead compound 1 (Fig. 1).

Keywords

Bi-cyclic; Ion channel; Pain; TRPV4 antagonist; Thiazole; Transient Receptor Potential Vanilloid 4; Vanilloid receptor.

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