Peripheralized CB1 antagonists for ALD

描述(申请人提供)：这项研究项目的目的是开发外周限制性大麻素受体1(CB1R)拮抗剂来治疗酒精性脂肪变性。酗酒对许多器官都有有害影响，最明显的是肝脏会导致脂肪变性(AS)、脂肪性肝炎(ASH)和肝硬变(AC)。以前被认为是良性的，新兴的数据表明，AS本身就是一种病理状态。因此，抑制AS的药物对酒精性肝病(ALD)非常有用。拮抗CB1R是治疗ALD的有效策略。不幸的是，第一个被批准的CB1R拮抗剂利莫那班(SR141716)，作为一种减肥药片在欧洲推出，由于一些使用者的不良反应，包括抑郁和自杀念头，被撤回。然而，越来越多的证据表明，选择性抑制外周CB1R，避免可能的CNS相关副作用，在治疗涉及CB1R亚群的疾病中可能是有用的。因此，开发不能渗透血脑屏障(BBB)的外周限制性CB1R拮抗剂是治疗ALD和相关疾病的令人兴奋的策略，同时限制非组织选择性拮抗剂注意到的与中枢神经系统相关的不良事件。通过我们正在进行的计划，我们已经开发了基于二苯基嘌呤支架的高度有效和选择性的CB1R拮抗剂，这些药物可以进一步完善。这项建议的目的是改善这些化合物的类药物性质，通过四个具体目标确定进一步开发的临床前候选药物：(1)将对先前表征的CB1R拮抗剂的类似物进行外周选择性修饰。我们已经生产并报道了高效、选择性强、具有约3-7%大脑渗透率的化合物。其目标将是生产出更像药物的化合物，大脑渗透率为3%。(2)随后将对这些化合物进行药理学表征，包括确定ADMET和药代动力学特性，以生成体内疗效研究的优先列表。(3)由于非组织选择性CB1R拮抗剂产生与中枢神经系统相关的不良反应，通过AIM 2确定的化合物将被测试以阻断(-)-β-9-四氢大麻酚(THC)的作用，THC是一种有效的CB1R激动剂，用于运动活性、抗伤害性、低温和过敏性四联试验。在抑郁症动物模型中，这些化合物将在长期给药后得到进一步评估。(4)在AS的Lieber-DeCarli模型中进行疗效研究。将对与疗效相关的生物标志物进行评估。还将进行机制研究，以检查CB1R拮抗影响的信号通路。具有良好性能的候选化合物将被确定用于进一步开发。

DESCRIPTION (provided by applicant): The aim of this research project is to develop peripherally restricted cannabinoid receptor 1 (CB1R) antagonists for alcoholic steatosis. Alcohol abuse has detrimental effects on many organs, most notably the liver causing steatosis (AS), steatohepatitis (ASH), and cirrhosis (AC). Previously considered benign, emerging data suggest that AS is a pathological condition by itself. Thus, medications that inhibit AS will be extremely useful for alcoholic liver disease (ALD). Antagonism of CB1R is a validated strategy for treating ALD. Unfortunately, the first approved CB1R antagonist rimonabant (SR141716), which was introduced in Europe as an anti-obesity pill, was withdrawn due to adverse effects in some users including depression and suicidal ideation. However, a growing body of evidence suggests that selective inhibition of peripheral CB1R, avoiding possible CNS related side effects, may be useful in the treatment of diseases where this CB1R sub-population is implicated. Thus, development of peripherally restricted CB1R antagonists that cannot permeate the blood-brain barrier (BBB) is an exciting strategy for treating ALD and associated disorders while limiting the CNS-related adverse events noted with non-tissue selective antagonists. Through our ongoing program, we have developed highly potent and selective CB1R antagonists based on a diphenyl purine scaffold that are amenable to further refinement. The goal of this proposal is to improve on the drug-like properties of these compounds to identify preclinical candidates for further development through four specific aims: (1) Analogs of a previously characterized CB1R antagonist will be modified for peripheral selectivity. We have already produced and reported compounds that are highly potent, selective, and have ~3-7% brain penetration. The goal will be to produce compounds that are more drug-like with <3% brain penetration. (2) Pharmacological characterization of these compounds will follow, including establishment of ADMET and pharmacokinetic properties to generate a priority list for in vivo efficacy studies. (3) Since non-tissue selective CB1R antagonists produce CNS-related adverse effects, compounds identified through aim 2 will be tested for blocking the effect of (-)-¿-9-tetrahydrocannabinol (THC), which is a potent CB1R agonist in the tetrad assay of locomotor activity, antinociception, hypothermia, and catalepsy. These compounds will be further evaluated following chronic administration in an animal model of depression. (4) Efficacy studies will be performed in the Lieber-DeCarli model of AS. Efficacy related biomarkers will be evaluated. Mechanistic studies will be also performed to examine signaling pathways affected by CB1R antagonism. Candidate compounds with favorable properties will be identified for further development.