Jenrin Discovery, 2515 Lori Lane North, Wilmington, DE 19810, USA.
Bioorg Med Chem Lett. 2013 Sep 1;23(17):4751-60. doi: 10.1016/j.bmcl.2013.06.066. Epub 2013 Jul 4.
Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).
大麻素-1（CB1）受体的拮抗剂（反向激动剂）作为控制肥胖和相关代谢功能/肝脏疾病的新疗法具有广阔的前景。这些代表不同化学系列的药物具有穿透大脑的特性，因为最初认为治疗益处主要基于大脑受体相互作用。然而，该类唯一上市药物利莫那班具有令人不快的中枢神经系统副作用，导致其被撤出市场，随后其他临床候选药物的开发也很快终止。对这种方法的重新评估集中在中性或外周受限（PR）拮抗剂上。支持这些策略的药理学证据表明，即使不是全部，全球作用药物的大多数特性都可以被大脑存在很少的分子所捕获。本文讨论了可用于消除血脑屏障穿透性和识别大脑存在很少的潜在药物的方法（体外测定、组织分布和受体占有率测定、行为范式）。重点将放在支持所报道的药物确实是外周受限的药理学证据上。这些类型化合物的显著例子包括：TM38837（未公开结构）；AM6545（8）；JD5037（15b）；RTI-12（19）。
