alicapistat (ABT-957) / AbbVie - LARVOL DELTA

Calcium-dependent pathway as a primary cause of hypoxic RGC damage in monkey retinal explants. (PubMed, PLoS One) - "Calcium-independent cathepsins do not contribute to RGC damage in monkey retinal explants cultured under hypoxia/reperfusion. In contrast, calcium influx from extracellular sources plays a critical role in inducing RGC damage. Elevated intracellular calcium levels could activate calpains, leading to RGC damage; however, other calcium-dependent pathways might also be involved in this process."

Journal • Preclinical • Glaucoma • Ophthalmology • Retinal Disorders • CAPN1 • CTSS

Extending the Calpain-Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma. (PubMed, ACS Pharmacol Transl Sci) - "AD clinical trials were recently halted on alicapistat, a selective calpain-1 inhibitor, because of insufficient exposure of neurons to the drug...No clear advantage was shown by selective versus nonselective calpain inhibitors in these studies. The lack of recognition of the ability of calpain inhibitors to protect the BBB may have led to the premature abandonment of this therapeutic approach in AD clinical trials and requires further mechanistic studies of cerebrovascular protection by calpain-1 inhibitors."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dementia • Ischemic stroke • Reperfusion Injury • Vascular Neurology • ALDH2 • CTSB • GFAP • MMP9 • NOS3

Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability. (PubMed, Bioorg Med Chem Lett) - "Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies."

Journal • Alzheimer's Disease • CNS Disorders

Synthesis of α-Ketoamide-based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents. (PubMed, ChemMedChem) - "Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment...This allowed for the exploration of stereoselective inhibition of calpain-1, with ( 1c ) (IC 50  = 78 nM) being significantly more potent than ( 1g ). Moreover, inhibitor  1c  restored cognitive function in amnestic mice."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CTSS

Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies. (PubMed, Clin Pharmacol Drug Dev) - "Alicapistat at 400- or 800-mg twice-daily doses had no effect on REM sleep parameters, whereas the active control, donepezil at 10 mg twice daily, affected sleep parameters. There were no clinically significant changes in vital signs and laboratory measurements. The lack of an effect of alicapistat on sleep suggests that concentrations in the CNS were inadequate or that preclinical studies do not predict alicapistat effects in humans."

Clinical • Journal • P1 data • PK/PD data • Alzheimer's Disease • CNS Disorders