Discovery of small molecule antagonists of TRPV1

  • Bioorg Med Chem Lett. 2004 Jul 16;14(14):3631-4. doi: 10.1016/j.bmcl.2004.05.028.
Harshad K Rami  1 ,  Mervyn Thompson ,  Paul Wyman ,  Jeffrey C Jerman ,  Julie Egerton ,  Stephen Brough ,  Alexander J Stevens ,  Andrew D Randall ,  Darren Smart ,  Martin J Gunthorpe ,  John B Davis
Affiliations
  • 1. Neurology and GI CEDD, New Frontiers Science Park, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. [email protected]
PMID: 15203132 DOI: 10.1016/j.bmcl.2004.05.028
Abstract

Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR CA(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor.

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