2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency.
A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.
Borthwick
Alan D
AD
Department of Medicinal Chemistry, Cardiovascular and Urogenital Centre of Excellence for Drug Discovery, Stevenage, UK. alan.d.borthwick@drugmoldesign.com
Davies
Dave E
DE
Exall
Anne M
AM
Hatley
Richard J D
RJ
Hughes
Jennifer A
JA
Irving
Wendy R
WR
Livermore
David G
DG
Sollis
Steve L
SL
Nerozzi
Fabrizio
F
Valko
Klara L
KL
Allen
Michael J
MJ
Perren
Marion
M
Shabbir
Shalia S
SS
Woollard
Patrick M
PM
Price
Mark A
MA
D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001667:Binding, Competitive; D001682:Biological Availability; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
C513156:2-(2,4-difluorophenyl)-2-(3-(2,3-dihydro-1H-inden-2-yl)-6-(2-methylpropyl)-2,5-dioxo-1-piperazinyl)-N,N-dimethylethanamide; D065092:Antidiuretic Hormone Receptor Antagonists; D007192:Indenes; D010879:Piperazines; D018045:Receptors, Oxytocin; D010121:Oxytocin