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Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2020-10-21 , DOI: 10.1016/j.bmcl.2020.127624
Stephen E Mercer 1 , Prasad V Chaturvedula 2 , Charles M Conway 3 , Deborah A Cook 4 , Carl D Davis 5 , Sokhom S Pin 6 , Robert Macci 7 , Richard Schartman 8 , Laura J Signor 9 , Kimberly A Widmann 9 , Valerie J Whiterock 9 , Ping Chen 10 , Cen Xu 5 , John J Herbst 9 , Walter A Kostich 11 , George Thalody 8 , John E Macor 12 , Gene M Dubowchik 3
Affiliation  

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP Ki = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (FPO = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP Ki = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat FPO = 17%).



中文翻译:

Azepino-吲唑类是降钙素基因相关肽(CGRP)受体拮抗剂

降钙素基因相关肽(CGRP)受体拮抗剂在临床上已被证明是治疗偏头痛的有效方法。Zavegepant(BHV-3500,BMS-742413)是CGRP受体(hCGRP K i = 0.023 nM)的高亲和力拮抗剂,尽管显示大鼠口服生物利用度低(F PO = 1.7%)。我们使用zavegepant作为模板,试图通过设计一系列旨在减少可旋转键数的a庚酮来提高口服生物利用度。这些努力导致发现了化合物21,该化合物能够主要维持高亲和力结合(hCGRP K i= 0.100 nM)和the猴脸部血流测定的体内功效,同时大大提高了口服生物利用度(大鼠F PO = 17%)。

更新日期:2020-10-30
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