Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.,Journal of Medicinal Chemistry

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Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-08 , DOI: 10.1021/acs.jmedchem.0c00366
Xiawei Dang _{1,

2} , Lihong Zhang ₂ , Antonietta Franco _{2,

3} , Jiajia Li ₂ , Agostinho G Rocha ₂ , Sriram Devanathan ₃ , Roland E Dolle _{3,

4} , Peter R Bernstein ₅ , Gerald W Dorn _{2,

3}

Affiliation

Mutations in the mitochondrial fusion protein mitofusin (MFN) 2 cause the chronic neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A), for which there is currently no treatment. Small-molecule activators of MFN1 and MFN2 enhance mitochondrial fusion and offer promise as therapy for this condition, but prototype compounds have poor pharmacokinetic properties. Herein, we describe a rational design of a series of 6-phenylhexanamide derivatives whose pharmacokinetic optimization yielded a 4-hydroxycyclohexyl analogue, 13, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of 13cis- and trans-4-hydroxycyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the trans form, 13B. Preclinical absorption, distribution, metabolism, and excretion (ADME) and in vivo target engagement studies of 13B support further development of 6-phenylhexanamide derivatives as therapeutic agents for human CMT2A.

中文翻译：

发现6-苯基己酰胺衍生物作为强效的立体选择性线粒体融合素活化剂，用于治疗线粒体疾病。

线粒体融合蛋白线粒体融合素（MFN）2的突变会导致慢性神经退行性疾病2型Charcot-Marie-Tooth病（CMT2A），目前尚无治疗方法。MFN1和MFN2的小分子激活剂可增强线粒体融合，并有望作为治疗该病的方法，但原型化合物的药代动力学性能较差。在这里，我们描述了一系列6-苯基己酰胺衍生物的合理设计，其药代动力学优化产生了4-羟基环己基类似物13，具有临床前候选药物的效力，选择性和口服生物利用度。研究13顺式-和反式-4-羟基环己基异立体异构体意外地揭示了反式13B的功能和蛋白质结合。临床上对13B的吸收，分布，代谢和排泄（ADME）和体内靶标参与研究支持进一步开发6-苯基己酰胺衍生物作为人类CMT2A的治疗剂。

更新日期：2020-07-09

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