Document Report Card

ID: ALA1151753

Journal: J Med Chem

Title: New benzylureas as a novel series of potent, nonpeptidic vasopressin V2 receptor agonists.

Authors: Yea CM, Allan CE, Ashworth DM, Barnett J, Baxter AJ, Broadbridge JD, Franklin RJ, Hampton SL, Hudson P, Horton JA, Jenkins PD, Penson AM, Pitt GR, Rivière P, Robson PA, Rooker DP, Semple G, Sheppard A, Haigh RM, Roe MB.

Abstract: Vasopressin (AVP) is a hormone that stimulates an increase in water permeability through activation of V2 receptors in the kidney. The analogue of AVP, desmopressin, has proven an effective drug for diseases where a reduction of urine output is desired. However, its peptidic nature limits its bioavailability. We report herein the discovery of potent, nonpeptidic, benzylurea derived agonists of the vasopressin V2 receptor. We describe substitutions on the benzyl group to give improvements in potency and subsequent modifications to the urea end group to provide improvements in solubility and increased oral efficacy in a rat model of diuresis. The lead compound 20e (VA106483) is reported for the first time and has been selected for clinical development.

CiteXplore: 19053774

DOI: 10.1021/jm8008162