Dysregulation of calpain has been observed in various pathophysiological processes like stroke, traumatic brain injury, Alzheimer's, Huntington's, Parkinson's Disease and Multiple Sclerosis. In Alzheimer’s Disease hyperactivated calpain leads to synaptic dysfunction, b-amyloid production, tau pathology and neurodegeneration. Inhibition of calpain, either via the natural inhibitor Calpastatin or using low molecular weight calpain inhibitors, has been shown to ameliorate the pathology in AD-relevant models. Two major challenges in former calpain inhibitor programs have been the selectivity of the inhibitors for calpain versus closely related enzymes like cathepsins and the identification of a drug like warhead interacting with the active site cysteine.<br/>Starting from published lead compounds with decent potency but low selectivity and with a poor ADME profile, systematic modification of inhibitor backbone, attached side chains and the active site directed warhead lead to significantly improved inhibitors regarding potency and selectivity, however, species dependent low oral bioavailability remained an issue. Identification of the metabolic hot spot and subsequent dedicated structural modification led to calpain inhibitors with significantly improved oral bioavailability across species, while maintaining the favorable activity and selectivity profile. Advanced lead candidates were identified which featured broad efficacy in AD related preclinical animal models combined with an excellent safety profile in toxicology. The efforts finally led to a clinical candidate with the potential for proof of concept studies in Alzheimer’s Disease patients with a first-in-class calpain inhibitor.

Discovery of novel potent and selective first in class calpain inhibitors for the potential treatment of neurodegenerative disorders

256th National Meeting (2018)

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