Department of Molecular Sciences and Candidate Optimization (MSCO), Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2012 Jul 15;22(14):4723-7. doi: 10.1016/j.bmcl.2012.05.074. Epub 2012 Jun 1.
We have systematically studied the effects of varying the central unnatural amino acid moiety on CGRP receptor antagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23, a potent CGRP receptor antagonist with only weak CYP3A4 inhibition. Unlike the triptans, compound 23 did not cause active constriction of ex vivo human cerebral arteries. At doses of 0.3-1 mg/kg (s.c.), 23 showed robust inhibition of CGRP-induced increases in marmoset facial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1H-indazol-5-yl substituted alanine as a tyrosine surrogate.
我们系统性地研究了一系列脲基酰胺中改变中心非天然氨基酸部分对 CGRP 受体拮抗剂效力和 CYP 抑制的影响。在这封信中，我们报告了化合物 23 的发现，它是一种有效的 CGRP 受体拮抗剂，对 CYP3A4 的抑制作用很弱。与曲坦类药物不同，化合物 23 不会引起离体人类脑血管的主动收缩。在 0.3-1mg/kg（sc）剂量下，23 显示出对 CGRP 诱导的狨猴面部血流量增加的强烈抑制作用，这是一种已验证的偏头痛模型。脲基酰胺 23 来源于一种新型氨基酸，1H-吲哚-5-基取代的丙氨酸作为酪氨酸的替代物。
