Department of Molecular Sciences and Candidate Optimization (MSCO), Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2013 Mar 15;23(6):1870-3. doi: 10.1016/j.bmcl.2013.01.011. Epub 2013 Jan 24.
Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%).
各种取代的吲唑和苯并恶唑酮氨基酸被研究作为高活性 CGRP 受体拮抗剂中的 D-酪氨酸替代物。化合物 3 源自 7-甲基吲唑核心，与未取代的吲唑类似物 1 相比，其 CGRP 结合效力提高了 30 倍。当以 0.03mg/kg SC 给药时，化合物 2（3 和其（S）-对映体的外消旋混合物）表现出对 CGRP 诱导的狨猴面部血流量增加的有效抑制作用，持续长达 105 分钟。该化合物具有有利的预测体外毒理学特征和良好的水溶解度。当作为鼻喷雾剂在兔子中给药时，3 被迅速吸收并显示出良好的鼻内生物利用度（42%）。
