2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics.
A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).
Borthwick
Alan D
AD
Department of Medicinal Chemistry, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K. alan.d.borthwick@gsk.com
Davies
Dave E
DE
Exall
Anne M
AM
Livermore
David G
DG
Sollis
Steve L
SL
Nerozzi
Fabrizio
F
Allen
Michael J
MJ
Perren
Marion
M
Shabbir
Shalia S
SS
Woollard
Patrick M
PM
Wyatt
Paul G
PG
D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012709:Serum Albumin / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014668:Vasotocin / Q000031:analogs & derivatives / Q000494:pharmacology
D065092:Antidiuretic Hormone Receptor Antagonists; D010879:Piperazines; D018045:Receptors, Oxytocin; D012709:Serum Albumin; C047046:atosiban; D014668:Vasotocin