SB-705498 is a potent, selective and orally bioavailable transient receptor potential vanilloid 1 (TRPV1) receptor antagonist with a pIC50 of 7.1. SB705498 potently inhibits capsaicin-induced activation of human TRPV1 expressed in 1321N1 cells or HEK293 cells with apparent pKi of 7.5 or 7.6, respectively. Coapplication of 100 nM SB705498 rapidly, completely and reversibly inhibits hTRPV1 expressed in HEK293 cells. Compared with placebo, SB-705498 reduced the area of capsaicin-evoked flare (P=0.0047). The heat pain threshold on non-sensitised skin was elevated following SB-705498 (estimated difference from placebo [95% confidence intervals]: 1.3 degrees C [0.07,2.53], P=0.019). Following capsaicin sensitisation, the heat pain threshold and tolerance were similar between SB-705498 and placebo. However, SB-705498 increased heat pain tolerance at the site of UVB-evoked inflammation (estimated difference from placebo: 0.93 degrees C [0.25,1.6], P=0.0054). The magnitude of the pharmacodynamic effects of SB-705498 appeared to be related to plasma concentration. These results indicate that SB-705498, at a clinically safe and well-tolerated dose, has target-specific pharmacodynamic activity in humans. These data provide the first clinical evidence that a TRPV1 antagonist may alleviate pain and hyperalgesia associated with inflammation and tissue injury.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO ≥70 mg/mL|
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