The Discovery\nof MORF-627, a Highly Selective Conformationally-Biased\nZwitterionic Integrin αvβ6 Inhibitor for Fibrosis

Inhibition of integrin αvβ6 is a promising\napproach\nto the treatment of fibrotic disease such as idiopathic pulmonary\nfibrosis. Screening a small library combining head groups that stabilize\nthe bent-closed conformation of integrin αIIbβ3 with αv\nintegrin binding motifs resulted in the identification of hit compounds\nthat bind the bent-closed conformation of αvβ6. Crystal\nstructures of these compounds bound to αvβ6 and related\nintegrins revealed opportunities to increase potency and selectivity,\nand these efforts were accelerated using accurate free energy perturbation\n(FEP+) calculations. Optimization of PK parameters including permeability,\nbioavailability, clearance, and half-life resulted in the discovery\nof development candidate MORF-627, a highly selective inhibitor of\nαvβ6 that stabilizes the bent-closed conformation and\nhas good oral PK. Unfortunately, the compound showed toxicity in a\n28-day NHP safety study, precluding further development. Nevertheless,\nMORF-627 is a useful tool compound for studying the biology of integrin\nαvβ6.