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
  • 1. Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan. Electronic address: [email protected].
  • 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.