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.)
Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-17 , DOI: 10.1021/acs.jmedchem.9b01478 Patrick Schnider 1 , Caterina Bissantz 1 , Andreas Bruns 1 , Cosimo Dolente 1 , Erwin Goetschi 1 , Roland Jakob-Roetne 1 , Basil Künnecke 1 , Thomas Mueggler 1 , Wolfgang Muster 1 , Neil Parrott 1 , Emmanuel Pinard 1 , Hasane Ratni 1 , Céline Risterucci 1 , Mark Rogers-Evans 1 , Markus von Kienlin 1 , Christophe Grundschober 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-17 , DOI: 10.1021/acs.jmedchem.9b01478 Patrick Schnider 1 , Caterina Bissantz 1 , Andreas Bruns 1 , Cosimo Dolente 1 , Erwin Goetschi 1 , Roland Jakob-Roetne 1 , Basil Künnecke 1 , Thomas Mueggler 1 , Wolfgang Muster 1 , Neil Parrott 1 , Emmanuel Pinard 1 , Hasane Ratni 1 , Céline Risterucci 1 , Mark Rogers-Evans 1 , Markus von Kienlin 1 , Christophe Grundschober 1
Affiliation
|
We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.
中文翻译：
发现Balovaptan，一种血管加压素1a受体拮抗剂，用于治疗自闭症谱系障碍。
我们最近报道了一种不适合完全发育的有效，选择性和脑渗透性V1a受体拮抗剂的发现。然而，在一项机制探索性研究中，发现该化合物可改善自闭症谱系障碍成年人的社会行为指标。在这里，我们描述了产生具有改善的药代动力学性质的三唑并苯并二氮杂卓的脚手架跳跃。平衡效能和选择性同时最小化P-gp介导的外排的关键是微调氢键受体的碱性。通过药理磁共振成像在大鼠中确定V1a拮抗剂特异性脑活动模式在指导优化工作中发挥了开创性作用，最终发现了巴洛伐坦（RG7314，RO5285119）1。在一项针对自闭症谱系障碍成年人的为期12周的临床2期研究中，巴洛伐坦证明了Vineland-II适应行为量表的改进，该量表是包括沟通，社交和日常生活技能的次要终点。Balovaptan于2018年8月进入3期临床开发。
更新日期：2020-01-17
中文翻译：
发现Balovaptan，一种血管加压素1a受体拮抗剂，用于治疗自闭症谱系障碍。
我们最近报道了一种不适合完全发育的有效，选择性和脑渗透性V1a受体拮抗剂的发现。然而，在一项机制探索性研究中，发现该化合物可改善自闭症谱系障碍成年人的社会行为指标。在这里，我们描述了产生具有改善的药代动力学性质的三唑并苯并二氮杂卓的脚手架跳跃。平衡效能和选择性同时最小化P-gp介导的外排的关键是微调氢键受体的碱性。通过药理磁共振成像在大鼠中确定V1a拮抗剂特异性脑活动模式在指导优化工作中发挥了开创性作用，最终发现了巴洛伐坦（RG7314，RO5285119）1。在一项针对自闭症谱系障碍成年人的为期12周的临床2期研究中，巴洛伐坦证明了Vineland-II适应行为量表的改进，该量表是包括沟通，社交和日常生活技能的次要终点。Balovaptan于2018年8月进入3期临床开发。
京公网安备 11010802027423号