Lead Optimization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease

Vivreon Biosciences NIA SBIR PA Project Summary Vivreon Biosciences is pleased to apply for NIA SBIR Solicitation PA Vivreon Biosciences is an innovative life sciences company that is developing a series of novel small molecule Ca channel inhibitors for the treatment of Alzheimer s disease AD Our lead compound series achieves neuroprotection by an entirely new mechanism inhibition of Ca release activated Ca CRAC channels to block microgliosis Vivreon seeks NIA funding to bridge the gap between discovery and development We will optimize our promising lead compound series through medicinal chemistry Upon successful completion of the program our preclinical candidate will be the first to specifically target the CRAC pathway for neuroprotection in AD thus comprising an entirely new tool in the battle against AD Vivreon has discovered a lead compound series with oral bioavailability that penetrates into the central nervous system CNS very efficiently shows no neurotoxicity in the Irwin test of CNS integrity and demonstrates neuroprotection in a mouse model of microgliosis experimental autoimmune encephalitis The lead series inhibits microgliosis by blocking CRAC channel activity with nM potency suppressing M NF B activity while preserving M phagocytosis We will improve on these favorable properties through medicinal chemistry lead optimization followed by biological screening Our lead presents several routes for modification that could lead to improved drug like properties and these routes will be pursued to identify a preclinical candidate molecule suitable for future Investigational New Drug IND enabling studies The candidate will be identified using an animal model suitable for AD XFAD Dr Blurton Jones University of California Irvine The final aim for this proposal is synthesis and characterization of the first CRAC channel inhibitor for AD therapy Vivreon Biosciences NIA SBIR PA Project Narrative Current Alzheimer s disease AD therapies act on neurons only to alleviate symptoms of the disease without slowing disease progression Microglial associated genes are risk factors for AD and chronic microgliosis contributes to progressive neurodegeneration in AD Vivreon Biosciences is developing neuroprotective therapeutics to block pathogenic microgliosis by inhibiting microglial Ca release activated Ca CRAC channel activation for use in the treatment of AD