Design, syntheses, and biological evaluation of novel TRPV1 antagonists

ORGN 690

Nam-Jung Kim, stringfellow98@hanmail.net1, Dong-Jo Chang,, Hwayoung Yun, yunorganic@gmail.com1, Jaebong Jang, jaebong.jang@gmail.com1, Young Taek Han,, Yeon-Su Jeong2, Jin-kyu Choi2, Joo-Hyun Moh2, Sun-Young Kim2, and Young-Ger Suh, (1) College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul, 151-742, South Korea, (2) AmorePacific R&D Center, Gyunggi-Do, Korea, 449-900
The transient receptor potential vanilloid 1 (TRPV1) is a member of ion channels and is localized on primary afferent neurons as sensory neurons inervating the bladder and gut. Activation of TRPV1 on sensory neurons by chemical stimulants including capsaicin and resiniferatoxin, as well as low pH(<6) ,heat(>42C), and nucleosides such as ATP leads to an influx of Ca2+ and Na+ ions through the channel, causing depolarization of the cell and transmission of painful stimuli. Therefore considerable efforts toward the development of a novel analgesic targeted for TRPV1 have been continued. However, the side effects, such as hypothermia and low oral bioavailability of capsaicin as TRPV1 agonist limited therapeutic uses. On the basis of the previous studies on TRPV1 agonists and antagonists, we have looked for the non-vanilloid TRPV1 antagonists by developing the ideal vanilloid equivalents, which might provide the perfect analgesic effects without the side effects caused by TRPV1 agonists. In our efforts toward the discovery of new analgesic agents, we identified SC-0030 as potent and selective TRPV1 antagonists. In addition, we have made every possible effort to develop next generation TRPV1 antagonists on the basis of 3D-QSAR and bioisosterism. Recently, we have developed a series of novel non-vanilloid TRPV1 antagonists such as SC-0646(IC50=14nM), SC-0614(IC50=28nM), resulting from focused modification on the lipophilic region and multiple H-bonding region.