155172-73-9Relevant articles and documents
2,5-Diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics
Borthwick, Alan D.,Davies, Dave E.,Exall, Anne M.,Livermore, David G.,Sollis, Steve L.,Nerozzi, Fabrizio,Allen, Michael J.,Perren, Marion,Shabbir, Shalia S.,Woollard, Patrick M.,Wyatt, Paul G.
, p. 6956 - 6969 (2007/10/03)
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 (pKi > 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 (pKi = 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 DR10 = 0.44 mg/kg iv).