当前位置:
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-02-14 , DOI: 10.1021/acs.jmedchem.9b01810 Gene M Dubowchik 1 , Charles M Conway 1 , Alison W Xin 1
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-02-14 , DOI: 10.1021/acs.jmedchem.9b01810 Gene M Dubowchik 1 , Charles M Conway 1 , Alison W Xin 1
Affiliation
The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.
中文翻译:
阻断CGRP偏头痛的急性和预防性治疗途径:成功的演变。
降钙素基因相关肽(CGRP)在偏头痛病理生理中的关键作用已被确定于30年前,但是靶向疗法的成功临床开发直到最近才得以实现。该观点追溯了推进小分子CGRP受体拮抗剂(也称为速溶剂)所需的数十年的药物化学发展过程,包括目前的临床药物瑞格非特,vazegepant,ubrogepant和atogepant。提供临床上有效的CGRP信号传导阻滞需要克服多个挑战性障碍,包括击败与其受体具有亚纳摩尔亲和力的可观配体,设计具有扩展确认和多种药效的拮抗剂,同时保持溶解性和口服生物利用度,并达到提供接近最大CGRP受体覆盖率的循环游离血浆水平。描述了口服和鼻内给予剂的临床疗效以及可注射的CGRP单克隆抗体(mAb),以及最近受益于新的结构生物学数据的合成技术进展。第一种口服速效剂最近获得批准,预示着偏头痛治疗的新纪元。
更新日期:2020-02-14
中文翻译:
阻断CGRP偏头痛的急性和预防性治疗途径:成功的演变。
降钙素基因相关肽(CGRP)在偏头痛病理生理中的关键作用已被确定于30年前,但是靶向疗法的成功临床开发直到最近才得以实现。该观点追溯了推进小分子CGRP受体拮抗剂(也称为速溶剂)所需的数十年的药物化学发展过程,包括目前的临床药物瑞格非特,vazegepant,ubrogepant和atogepant。提供临床上有效的CGRP信号传导阻滞需要克服多个挑战性障碍,包括击败与其受体具有亚纳摩尔亲和力的可观配体,设计具有扩展确认和多种药效的拮抗剂,同时保持溶解性和口服生物利用度,并达到提供接近最大CGRP受体覆盖率的循环游离血浆水平。描述了口服和鼻内给予剂的临床疗效以及可注射的CGRP单克隆抗体(mAb),以及最近受益于新的结构生物学数据的合成技术进展。第一种口服速效剂最近获得批准,预示着偏头痛治疗的新纪元。