Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery of an Indane analogue (12) with a less restrictive structure–activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life (t_1/2) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t_1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.

中文翻译：

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发现 Aficamten (CK-274)，一种用于治疗肥厚型心肌病的下一代心肌肌球蛋白抑制剂

心脏肌节的过度收缩对于遗传性肥厚性心肌病的潜在病理性肥大和纤维化可能是必不可少的。Aficamten (CK-274) 是一种新型心肌肌球蛋白抑制剂，是从二氢吲哚化合物1的优化中发现的。优化的重要进展是发现了具有较少限制性结构-活性关系的茚满类似物 ( 12 )，允许快速改善类药物特性。Aficamten 旨在提供适用于每天一次 (qd) 给药的预测人类半衰期 ( t _1/2 )，在两周内达到稳态，没有实质性的细胞色素 P450 诱导或抑制，并具有广泛的治疗窗在体内具有明确的药代动力学/药效学关系。在 I 期临床试验中，aficamten 证明了人类t _1/2与预测相似，并且能够在所需的两周窗口内达到稳态浓度。