SB-705498的生物活性

SB-705498 is a potent, selective and orally bioavailable transient receptor potential vanilloid 1 (TRPV1) receptor antagonist with a pIC50 of 7.1.
IC50 value: 7.1 (pIC50)
Target: TRPV1
SB-705498 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 SB-705498 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.

相關(guān)文獻

[1]. Martin J. Gunthorpe, Sara Luis Hannan, Darren Smart et al. Characterization of SB-705498, a Potent and Selective Vanilloid Receptor-1 (VR1/TRPV1) Antagonist That Inhibits the Capsaicin-, Acid-, and Heat-Mediated Activation of the Receptor. JPET June 2007 vol. 321 no. 3 1183-1192.

[2]. Chizh BA, O'Donnell MB, Napolitano A et al. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain. 2007 Nov;132(1-2):132-41.

[3]. Rami HK, Thompson M, Stemp G et al. Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3287-91.

[4]. Use Of SB-705498 In The Acute Treatment Of Migraine.