The P2X3 receptor is an ATP-gated ion channel expressed on primary afferent neurons that sense painful stimuli (nociceptors), with limited receptor expression in other tissues. This selective expression pattern makes the P2X3 receptor an attractive, non-prostanoid analgesic target with the potential to provide a safe treatment of chronic pain states such as occurs in osteoarthritis. Producing candidates with reduced potential for safety-related findings vs. lead compound MK-3901 was a primary driver for the team. Specifically targeted were decreasing the potential for drug-drug interaction (reversible CYP2C9 and time-dependent CYP3A4 inhibition), hyperbilirubinemia (UGT1A1 inhibition), and reducing the projected efficacious exposure through improvement of potency and/or lowering of plasma protein binding. To this end, incorporation of the central pyridinone drastically lowered plasma protein binding and ultimately enabled the production of compounds with improved <i>in vivo</i> potency. A concurrent strategy to eliminate the metabolic soft-spots of MK-3901, via truncation of the 2-pyridyl isoxazoline and replacement of the 5-methylpyridine, led to the identification of compounds with favorable pharmacokinetics. Furthermore, incorporation of the tertiary hydroxyl and oxadiazole groups allowed for diminished UGT1A1 activity and CYP inhibition/ induction potential. The culmination of these findings led to the discovery of the second generation P2X3 pre-clinical candidate, MK-2548. Key decision points for the program will be highlighted, including where potential candidates were deprioritized based on data indicating a lower POS due to projected safety-related risks.

Discovery of MK-2548: A P2X3 receptor antagonist for the treatment of chronic pain

251st National Meeting (2016)

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