Discovery of Potent, Selective, and Short-Acting Peptidic V₂ Receptor Agonists

The vasopressin analogue desmopressin (desamino-d-arginine⁸ vasopressin, dDAVP, 1) is a potent vasopressin 2 (V₂) receptor (V₂R) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis, and hyponatremia. In search of novel, potent, selective, and short-acting peptidic V₂R agonists, we synthesized a series of C-terminally truncated analogues of [Val⁴]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge. The peptides were evaluated for in vitro potency at the human V₂ receptor, selectivity versus the related receptors (human vasopressin 1a receptor, human vasopressin 1b receptor, and human oxytocin receptor), and pharmacokinetic profiles in rodents and other higher species. The truncated analogues show excellent potency at the V₂R, increased systemic clearance, and shorter half-life in rats. Two compounds 19 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-Agm) and 38 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-d-Arg-NEt₂) have been selected for clinical development for nocturia.