Rational Drug Design Leading to the Identification of a Potent 5-HT(2C) Agonist Lacking 5-HT(2B) Activity

ACS Med Chem Lett. 2011 Dec 8;2(12):929-932. doi: 10.1021/ml200206z.

Gang Chen ¹, Sung Jin Cho, Xi-Ping Huang, Niels H Jensen, Andreas Svennebring, Maria F Sassano, Bryan L Roth, Alan P Kozikowski

Affiliations

Affiliation

1 Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (M/C781), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7230.

PMID: 22778800 DOI: 10.1021/ml200206z

Abstract

The 5-HT(2C) receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT(2C) receptor agonists. After expanding our structure-function library, we were able to combine our datasets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT(2B)/5-HT(2C) agonists, which has led to the identification of a highly selective 5-HT(2C) agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC(50) of 55 nM and no detectable agonism at the 5-HT(2B) receptor.

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