Analgesic potential of TRPV1 antagonists

The discovery of TRPV1 antagonists as a new class of analgesic agents for the treatment of chronic pathological pain has been pursued aggressively across the pharmaceutical industry. This effort has led to the identification of several TRPV1 antagonists that have entered clinical trials, including ABT-102 (Abbott), SB-705498 (GSK), AMG-517 (Amgen), MK2295 (Merck/Neurogen), and GRC-6211 (Lilly/Glenmark). Using the published structures for ABT-102, SB-705498, AMG-517, and lead compounds representing six additional TRPV1 antagonist chemotypes, a pharmacophore model that describes the common structural features found in potent TRPV1 antagonists was established. The TRPV1 antagonist pharmacophore fits within the pore region of a TRPV1 receptor homology model, with critical hydrogen bond interactions proposed between the TRPV1 antagonist pharmacophore and Tyr 667 on helix six. In spite of the putative common binding site for all TRPV1 antagonists included in this particular TRPV1 pharmacophore, these ligands have demonstrated that they can still offer distinct pharmacological profiles, likely due to differences in their pharmacokinetic profiles. This is highlighted by differences in temperature elevation observed when comparing the clinical candidates ABT-102 and AMG-517. (C) 2009 Elsevier Inc. All rights reserved.