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

Jeewoo Lee, 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

Index: J. Med. Chem. 46(14) , 3116-26, (2003)

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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.