Neuroscience and Pain Research, Global Pharmaceutical Research and Development, Dept. R4DE AP9A/L-15, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA.
Bioorg Med Chem. 2010 Jul 1;18(13):4821-9. doi: 10.1016/j.bmc.2010.04.099. Epub 2010 May 10.
The synthesis and structure-activity relationships of a series of 5-monosubstituted and 4,5-disubstituted 2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor are described. The 7-hydroxy group of the tetrahydronaphthyl moiety on the 2-amino substituent of the oxazole ring was important for obtaining excellent in vitro potency at the human TRPV1 receptor, while a variety of alkyl and phenyl substituents at the 4- and 5-positions of the oxazole ring were well tolerated and yielded potent TRPV1 antagonists. Despite excellent in vitro potency, the 5-monosubstituted compounds suffered from poor pharmacokinetics. It was found that 4,5-disubstitution on the oxazole ring was critical to the improvement of the overall pharmacokinetic profile of these analogues, which led to the discovery of compound (R)-27, a novel TRPV1 antagonist with good oral activity in preclinical animal models of pain.
描述了一系列 5-单取代和 4,5-二取代 2-芳基氨基恶唑作为新型瞬时受体电位香草酸 1（TRPV1）受体拮抗剂的合成和构效关系。恶唑环 2-氨基取代基上的四氢萘基部分的 7-羟基对于获得对人 TRPV1 受体的优异体外活性非常重要，而恶唑环的 4-和 5-位的各种烷基和苯基取代基则具有良好的耐受性，并产生了有效的 TRPV1 拮抗剂。尽管具有优异的体外活性，但 5-单取代化合物的药代动力学性能较差。研究发现，恶唑环上的 4,5-二取代对于改善这些类似物的整体药代动力学特性至关重要，这导致了化合物 (R)-27 的发现，这是一种新型 TRPV1 拮抗剂，在疼痛的临床前动物模型中具有良好的口服活性。
