Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen activated protein family member (MAP3K) that upon stimulation activates the p38- and JNK-pathways, leading to acute ischemia/reperfusion injury. Structure-based drug design (SBDD) in parallel with deconstruction and re-optimization enabled the identification of a novel chemotype with a unique hinge-binding element. This yielded a series of compounds that were potent ASK1 inhibitors with desirable drug-like properties. Lead compounds from this series showed excellent oral bioavailability in a rat PK study and demonstrated reduction of infarct size in a Langendorff isolated perfused heart model of cardiac injury. Herein we describe the discovery of these novel ASK1 inhibitors and efficacy in the <i>ex vivo</i> model.

Identification of a novel chemotype of ASK1 inhibitors for heart failure utilizing structure-based drug design

253rd National Meeting (2017)

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