New benzylureas as a novel series of potent, nonpeptidic vasopressin V2 receptor agonists.
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.
Yea
Christopher M
CM
Vantia Ltd, Southampton Science Park, Southampton SO16 7NP, United Kingdom. chris.yea@vantiatherapeutics.com
Allan
Christine E
CE
Ashworth
Doreen M
DM
Barnett
James
J
Baxter
Andy J
AJ
Broadbridge
Janice D
JD
Franklin
Richard J
RJ
Hampton
Sally L
SL
Hudson
Peter
P
Horton
John A
JA
Jenkins
Paul D
PD
Penson
Andy M
AM
Pitt
Gary R W
GR
Rivière
Pierre
P
Robson
Peter A
PA
Rooker
David P
DP
Semple
Graeme
G
Sheppard
Andy
A
Haigh
Robert M
RM
Roe
Michael B
MB
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*
D017483:Receptors, Vasopressin; D014508:Urea