Peripheralized CB1 antagonists for ALD

描述（由申请人提供）：本研究项目的目的是开发用于酒精性脂肪变性的外周限制性大麻素受体1（CB1R）拮抗剂。酒精滥用对许多器官有有害影响，最明显的是引起脂肪变性（AS）、脂肪性肝炎（ASH）和肝硬化（AC）的肝脏。以前被认为是良性的，新的数据表明，AS本身是一种病理状态。因此，抑制AS的药物对酒精性肝病（ALD）非常有用。CB1R的拮抗作用是治疗ALD的有效策略。不幸的是，第一个批准的CB1R拮抗剂利莫那班（SR141716），这是在欧洲推出的抗肥胖药丸，被撤回，由于在一些用户的不良反应，包括抑郁症和自杀意念。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相关的副作用，可能是有用的，在疾病的治疗中，该CB1R亚群牵连。因此，不能渗透血脑屏障（BBB）的外周限制性CB1R拮抗剂的开发是治疗ALD和相关疾病同时限制非组织选择性拮抗剂所注意到的CNS相关不良事件的令人兴奋的策略。通过我们正在进行的项目，我们已经开发出基于二苯基嘌呤支架的高效和选择性CB1R拮抗剂，这些拮抗剂可以进一步改进。该提案的目标是改善这些化合物的药物样性质，以通过以下四个具体目标来鉴定用于进一步开发的临床前候选物：（1）将修饰先前表征的CB1R拮抗剂的类似物以用于外周选择性。我们已经生产并报道了高度有效，选择性和约3 - 7%脑渗透的化合物。目标将是生产更像药物的化合物，其大脑渗透率<3%。(2)随后将对这些化合物进行药理学表征，包括建立ADMET和药代动力学特性，以生成体内疗效研究的优先级列表。(3)由于非组织选择性CB1R拮抗剂产生CNS相关的不良作用，因此将测试通过目的2鉴定的化合物阻断（-）-<$-9-四氢大麻酚（THC）的作用，所述（-）-<$-9-四氢大麻酚（THC）在运动活性、抗伤害感受、体温过低和僵住症的四分体测定中是有效的CB1R激动剂。这些化合物将在抑郁症动物模型中长期给药后进一步评价。(4)将在Lieber-DeCarli AS模型中进行疗效研究。将评价疗效相关生物标志物。还将进行机制研究，以检查受CB1R拮抗作用影响的信号通路。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the first approved CB1R antagonist rimonabant (SR141716), which was introduced in Europe as an anti-obesity pill, was withdrawn due to adverse effects in some users including depression and suicidal ideation.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.