Discovery of small molecule antagonists of TRPV1 |
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Authors: | Rami Harshad K Thompson Mervyn Wyman Paul Jerman Jeffrey C Egerton Julie Brough Stephen Stevens Alexander J Randall Andrew D Smart Darren Gunthorpe Martin J Davis John B |
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Institution: | Neurology and GI CEDD, New Frontiers Science Park, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. harshad.rami@gsk.com |
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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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