Discovery of Substituted Human Urocortin 1 Analogs with Improved CRF2 Receptor Selectivity and Increased Efficacy in Preventing Skeletal Muscle Atrophy

Abstract

We have identified specific amino acid modifications of human Urocortin 1 (hUCN1) that lead to highly potent and selective Corticotropin Releasing Factor Receptor 2 (CRF2R) agonists that are efficacious in preventing skeletal muscle atrophy in animal models. We have demonstrated that the CRF2R versus CRF1R selectivity can be increased by modifying the 40 amino acid hUCN1 at amino acid positions 11, 12, 13, 35 and 39. Further improvement in drug properties, including reduced binding to the CRF binding protein, improved solubility, and improved in vivo potency, were achieved by modifying amino acids at positions 22, 23, 36, and 40. In vivo investigations of selected optimized hUCN1 analogs demonstrated significant anti-atrophy efficacy in a mouse casting model of hind leg muscle disuse atrophy.