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New Benzylureas as a Novel Series of Potent, Nonpeptidic Vasopressin V2 Receptor Agonists

2008; American Chemical Society; Volume: 51; Issue: 24 Linguagem: Inglês

10.1021/jm8008162

1520-4804

Christopher Yea, Christine E. Allan, Doreen M. Ashworth, James W. Barnett, Andy J. Baxter, Janice D. Broadbridge, Richard J. Franklin, Sally L. Hampton, Peter Hudson, John A. Horton, Paul D. Jenkins, Andy M. Penson, Gary R.W. Pitt, Pierre Rivière, P.A. Robson, David P. Rooker, Graeme Semple, A. W. Sheppard, R. Haigh, Michael B. Roe,

Circadian rhythm and melatonin

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.