Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain
Mechanistic and Pharmacological Characterization of PF-04457845: A Highly Potent and Selective Fatty Acid Amide Hydrolase Inhibitor That Reduces Inflammatory and Noninflammatory Pain
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DOI：
10.1124/jpet.111.180257
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发表时间：
2011-07-01
影响因子：
3.5
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Ahn, Kay;Smith, Sarah E.;Cravatt, Benjamin F.
内源性大麻素（endocannabinoid）anandamide主要由膜内酶脂肪酸酰胺水解酶（FAAH）降解。FAAH的药理学阻断已经成为一种潜在的有吸引力的策略，用于增强内源性大麻素信号传导并保留大麻素受体活化的有益作用，同时避免不期望的副作用，如体重增加和认知和运动控制障碍，用直接大麻素受体1激动剂观察到。在这里，我们报告了N-哒嗪-3-基-4-（3-{[5-（三氟甲基）吡啶-2-基]氧基}亚苄基）哌啶-1-甲酰胺（PF-04457845）的详细机制和药理学表征，这是一种高效和选择性的FAAH抑制剂。机制研究证实，PF-04457845是一种时间依赖性共价FAAH抑制剂，可使FAAH的催化丝氨酸亲核试剂发生氨基甲酰化。PF-04457845对人FAAH的抑制效力较高（k（无效）/K-i = 40，300 M（-1）s（-1）; IC50 = 7.2 nM），并且通过基于活性的蛋白质谱测定，在体内具有极高的选择性。PF-04457845经口给药在大鼠炎性[完全弗氏佐剂（CFA）]和非炎性（碘乙酸盐）疼痛模型中均产生强效抗伤害感受作用，最小有效剂量为0.1 mg/kg（CFA模型）。PF-04457845显示出较长的作用持续时间，因为以1 mg/kg单次经口给药显示出24 h的体内有效性，同时几乎完全抑制FAAH活性和脑中大麻素的最大持续升高。具有显著性意义的是，10 mg/kg PF-04457845给药小鼠对运动、僵住和体温无影响。基于其卓越的选择性和体内疗效，结合长期作用和最佳药代动力学特性，PF-04457845是治疗疼痛和其他神经系统疾病的临床候选药物。
The endogenous cannabinoid (endocannabinoid) anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH). Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining the beneficial effects of cannabinoid receptor activation, while avoiding the undesirable side effects, such as weight gain and impairments in cognition and motor control, observed with direct cannabinoid receptor 1 agonists. Here, we report the detailed mechanistic and pharmacological characterization of N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide (PF-04457845), a highly efficacious and selective FAAH inhibitor. Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAH's catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency (k(inact)/K-i = 40,300 M(-1)s(-1); IC50 = 7.2 nM) and is exquisitely selective in vivo as determined by activity-based protein profiling. Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory [complete Freund's adjuvant (CFA)] and noninflammatory (monosodium iodoacetate) pain models in rats, with a minimum effective dose of 0.1 mg/kg (CFA model). PF-04457845 displayed a long duration of action as a single oral administration at 1 mg/kg showed in vivo efficacy for 24 h with a concomitant near-complete inhibition of FAAH activity and maximal sustained elevation of anandamide in brain. Significantly, PF-04457845-treated mice at 10 mg/kg elicited no effect in motility, catalepsy, and body temperature. Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.