title: New benzylureas as a novel series of potent, nonpeptidic vasopressin V2 receptor agonists.
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.
authors.affiliation: Vantia Ltd, Southampton Science Park, Southampton SO16 7NP, United Kingdom. chris.yea@vantiatherapeutics.com
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Yea
authors.forename: Christine E
authors.initials: CE
authors.lastname: Allan
authors.forename: Doreen M
authors.initials: DM
authors.lastname: Ashworth
authors.forename: James
authors.initials: J
authors.lastname: Barnett
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Baxter
authors.forename: Janice D
authors.initials: JD
authors.lastname: Broadbridge
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Franklin
authors.forename: Sally L
authors.initials: SL
authors.lastname: Hampton
authors.forename: Peter
authors.initials: P
authors.lastname: Hudson
authors.forename: John A
authors.initials: JA
authors.lastname: Horton
authors.forename: Paul D
authors.initials: PD
authors.lastname: Jenkins
authors.forename: Andy M
authors.initials: AM
authors.lastname: Penson
authors.forename: Gary R W
authors.initials: GR
authors.lastname: Pitt
authors.forename: Pierre
authors.initials: P
authors.lastname: Rivière
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robson
authors.forename: David P
authors.initials: DP
authors.lastname: Rooker
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Andy
authors.initials: A
authors.lastname: Sheppard
authors.forename: Robert M
authors.initials: RM
authors.lastname: Haigh
authors.forename: Michael B
authors.initials: MB
authors.lastname: Roe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004231:Diuresis; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008956:Models, Chemical; D051381:Rats; D011910:Rats, Brattleboro; D017483:Receptors, Vasopressin / Q000819:agonists*; D012995:Solubility; D014508:Urea / Q000737:chemistry*
chemical_list: D017483:Receptors, Vasopressin; D014508:Urea