AF-353 (Ro-4)

Description: AF-353 (Ro-4; AF353) is a novel, highly potent, selective and orally bioavailable P2X3/P2X2/3 receptor antagonist with a pIC50 of 8.0 for both human and rat P2X3, and with a pIC50 of 7.3 for human P2X2/3. Antagonism of the P2X3 receptor is one of the potential therapeutic strategies for the management of neuropathic pain because P2X3 receptors are predominantly localized on small to medium diameter C- and Adelta-fiber primary afferent neurons, which are related to the pain-sensing system. Purinoceptors containing the P2X3 subunit (P2X3 homotrimeric and P2X2/3 heterotrimeric) are members of the P2X family of ion channels gated by ATP and may participate in primary afferent sensitization in a variety of pain-related diseases. The combination of a favourable pharmacokinetic profile with the antagonist potency and selectivity for P2X3 and P2X2/3 receptors suggests that AF-353 is an excellent in vivo tool compound for study of these channels in animal models and demonstrates the feasibility of identifying and optimizing molecules into potential clinical candidates, and, ultimately, into a novel class of therapeutics for the treatment of pain-related disorders.

References: Br J Pharmacol. 2010 Jul; 160(6):1387-1398.; BJU Int. 2012 Oct; 110(8 Pt B):E409-414.