TY - JOUR T1 - Pharmacological Characterization KLYP961, A Dual Inhibitor of Inducible and Neuronal Nitric Oxide Synthases JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.110.172817 SP - jpet.110.172817 AU - kent T Symons AU - Phan M Nguyen AU - Mark E Massari AU - JOHN V ANZOLA AU - LENA M STASSEWSKI AU - LI WANG AU - NAHID YAZDANI AU - STEVE DOROW AU - JERRY MUHAMMAD AU - MARCIANO SABLAD AU - NATASHA ROZENKRANTS AU - CELINE BONEFOUS AU - JOSEPH E PAYNE AU - PETER J RIX AU - ANDREW K SHIAU AU - STEWART A NOBLE AU - NICHOLAS D SMITH AU - CHRISTIAN A HASSIG AU - YAN ZHANG AU - TADIMETI S RAO Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/10/29/jpet.110.172817.abstract N2 - NO derived from nNOS and iNOS plays a key role in various pain and inflammatory states. KLYP961 inhibits the dimerization, and hence the enzymatic activity of human, primate and murine iNOS and nNOS (IC50 values: 50-400 nM), with marked selectivity against eNOS (IC50 >15000 nM). It has ideal drug like-properties, including excellent rodent and primate pharmacokinetics coupled with a minimal off-target activity profile. In mice, KLYP961 attenuated endotoxin-evoked increases in plasma nitrates, a surrogate marker of iNOS activity in viv, in a sustained manner (ED50 of 1 mg/kg, po.). KLYP961 attenuated pain behaviors in a mouse formalin model (ED50: 13 mg/kg, po), cold allodynia in the chronic constriction injury model (ED50: 25 mg/kg, po) or tactile allodynia in the spinal nerve ligation model (ED50: 30 mg/kg, po) with similar efficacy, but superior potency relative to gabapentin, pregabalin or duloxetine. Unlike morphine, the anti-allodynic activity of KLYP961 did not diminish upon repeated dosing. KLYP961 also attenuated carrageenin-induced edema and inflammatory hyperalgesia, and writhing response elicited by PBQ with efficacy and potency similar to those of celecoxib. In contrast to gabapentin, KLYP961 did not impair motor coordination at doses as high as up to 1000 mg/kg, po. KLYP961 also attenuated capsaicin-induced thermal allodynia in rhesus primates in a dose-related manner with a minimal effective dose < 10 mg/kg, po and a greater potency than gabapentin. In summary, KLYP961 represents an ideal tool with which to probe the physiological role of NO derived from iNOS and nNOS in human pain and inflammatory states. ER -