Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution

Charles A Blum; Xiaozhang Zheng; Harry Brielmann; Kevin J Hodgetts; Rajagopal Bakthavatchalam; Jayaraman Chandrasekhar; James E Krause; Daniel Cortright; David Matson; Marci Crandall; Chu K Ngo; Lawrence Fung; Marta Day; Mark Kershaw; Stéphane De Lombaert; Bertrand L Chenard

doi:10.1016/j.bmcl.2008.07.036

Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4573-7. doi: 10.1016/j.bmcl.2008.07.036. Epub 2008 Jul 15.

Authors

Charles A Blum¹, Xiaozhang Zheng, Harry Brielmann, Kevin J Hodgetts, Rajagopal Bakthavatchalam, Jayaraman Chandrasekhar, James E Krause, Daniel Cortright, David Matson, Marci Crandall, Chu K Ngo, Lawrence Fung, Marta Day, Mark Kershaw, Stéphane De Lombaert, Bertrand L Chenard

Affiliation

¹ Neurogen Corporation, 35 N. E. Industrial Road, Branford, CT 06405, USA. cablum@comcast.net

PMID: 18662872
DOI: 10.1016/j.bmcl.2008.07.036

Abstract

A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.

MeSH terms

Aminoquinolines / chemistry
Aminoquinolines / pharmacology*
Animals
Chemistry, Pharmaceutical / methods*
Dogs
Drug Design
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / chemistry
Inflammation / drug therapy
Kinetics
Models, Chemical
Molecular Conformation
Pain / drug therapy
Pharmaceutical Preparations / chemistry
Rats
TRPV Cation Channels / antagonists & inhibitors*
TRPV Cation Channels / chemistry

Substances

Aminoquinolines
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Pharmaceutical Preparations
TRPV Cation Channels
TRPV1 protein, human
TRPV1 receptor