Triazole oxytocin antagonists: Identification of an aryloxyazetidine replacement for a biaryl substituent.
A series of aryloxyazetidines, aryloxypyrrolidines and aryloxypiperidines were designed based on structural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in these new series. Several aryloxyazetidines also showed high levels of selectivity, with one compound, 25, displaying promising in vivo pharmacokinetics and significantly improved aqueous solubility over related compounds containing a biaryl substituent.
Brown
Alan
A
Discovery Chemistry, Pfizer Global Research and Development, Sandwich, United Kingdom. Alan.D.Brown@pfizer.com
Brown
T Bruce
TB
Calabrese
Andrew
A
Ellis
Dave
D
Puhalo
Nicholas
N
Ralph
Michael
M
Watson
Lesa
L
D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017483:Receptors, Vasopressin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D065092:Antidiuretic Hormone Receptor Antagonists; D001384:Azetidines; D017483:Receptors, Vasopressin; D014230:Triazoles; D010121:Oxytocin