N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor

  • J Med Chem. 2003 Jul 3;46(14):3116-26. doi: 10.1021/jm030089u.
Jeewoo Lee  1 ,  Jiyoun Lee ,  Myungshim Kang ,  Myoungyoup Shin ,  Ji-Min Kim ,  Sang-Uk Kang ,  Ju-Ok Lim ,  Hyun-Kyung Choi ,  Young-Ger Suh ,  Hyeung-Geun Park ,  Uhtaek Oh ,  Hee-Doo Kim ,  Young-Ho Park ,  Hee-Jin Ha ,  Young-Ho Kim ,  Attila Toth ,  Yun Wang ,  Richard Tran ,  Larry V Pearce ,  Daniel J Lundberg ,  Peter M Blumberg
Affiliations
  • 1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea. [email protected]
PMID: 12825950 DOI: 10.1021/jm030089u
Abstract

Isosteric replacement of the phenolic hydroxyl group in potent vanilloid receptor (VR1) agonists with the alkylsulfonamido group provides a series of compounds which are effective antagonists to the action of the capsaicin on rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells. In particular, compound 61, N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea was a full antagonist against capsaicin, displayed a K(i) value of 7.8 nM (compared to 520 nM for capsazepine and 4 nM for 5-iodoRTX), and showed excellent analgesic activity in mice. Structure-activity analysis of the influence of modifications in the A- and C-regions of 4-methylsulfonamide ligands on VR1 agonism/antagonism indicated that 3-fluoro substitution in the A-region and a 4-tert-butylbenzyl moiety in the C-region favored antagonism, whereas a 3-methoxy group in the A-region and 3-acyloxy-2-benzylpropyl moieties in the C-region favored agonism.