Abstract
P2X3 receptors are ATP‐gated channels with expression somewhat limited to primary afferent populations suspected of chronic sensitization in pain‐related disorders & offering therapeutic potential for antagonists (Ford, 2012, Purinergic Signal. 8:3–26). We describe preclinical PD & PK of AF‐219 (MW 353), a selective P2X3 antagonist optimized from an HTS lead.AF‐219 blocked ATP activation of rat & human P2X3 & P2X2/3 trimers in calcium flux & voltage‐clamp assays: IC50 values 25–200 nM; unlike A‐317491 & TNP‐ATP, allosteric inhibition of ATP was displayed. In homogenate binding studies, AF‐219, but not ATP or TNP‐ATP, displaced specific binding of [3H]AF‐353. At 10 μM no activity was seen at other P2X channels & in a battery of receptors, enzymes & channels.Favorable PK properties were observed for AF‐219 in rat, rabbit, dog & primate: high metabolic stability; oral availability (38–82 %F), elimination half‐life (t½ 1.5–7.6 h) & plasma free‐fraction (55–67% protein‐bound); predominant renal elimination (parent). AF‐219 was dose‐dependently efficacious (1–60 mg/kg, p.o. or s.c.; total plasma range 100–3000 ng/ml) in rodent models of hyperalgesia (neuropathic & inflammatory) or visceral hypersensitivity. The favorable PD, PK, & in vivo activity confirm AF‐219 as an excellent medicinal candidate to establish the role of P2X3 receptors in chronic pain and related conditions.
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