A-1165442

A-1165442 is a potent, competitive and orally available TRPV1 antagonist with an IC 50 of 9 nM for human TRPV1. In Vitro A-1165442 displays potent, competitive antagonism at recombinant human TRPV1 activated by capsaicin (IC 50 =9 nM) and incomplete blockade of acid-evoked response (62% block at 30 μM). A-1165442 possesses excellent selectivity (>100-fold) versus other members of the TRP family (TRPA1, TRPM8, TRPV2, TRPV3) and other receptors expressed in peripheral sensory neurons including P2X2/3, Cav2.2, Nav channels, and KCNQ2/3. A-1165442 shows minimal cross-reactivity upon evaluation (10 μM) in a broad screening panel (n=74, CEREP) of cell-surface receptors, ion channels, and enzymes. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo A-1165442 exhibits excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents. Oral administration of A-1165442 prevents capsaicin-induced nocifensive behaviors in rats, with an ED 50 of 9.5 μmol/kg corresponding to plasma concentration of 420 ng/mL (970 nM). A single dose of A-1165442 produces a robust effect on grip force, with an ED 50 of 35 μmol/kg measured 1 h postdosing. Repeated dosing of A-1165442 results in an increase in potency relative to acute analgesic efficacy. No significant changes in core body temperature is observed in conscious rats dosed with A-1165442 and this temperature-neutral profile is maintained in conscious dogs . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Form:Solid IC50& Target:IC50: 9 nM (human TRPV1)

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