ABSTRACT
A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2',6'-dimethyl-3'-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK(i) = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.
Subject(s)
Diketopiperazines/chemical synthesis , Morpholines/chemical synthesis , Oxytocin/metabolism , Receptors, Oxytocin/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cytochrome P-450 Enzyme Inhibitors , Diketopiperazines/administration & dosage , Diketopiperazines/pharmacokinetics , Diketopiperazines/pharmacology , Dogs , Female , Humans , In Vitro Techniques , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Morpholines/administration & dosage , Morpholines/pharmacokinetics , Radioligand Assay , Rats , Rats, Sprague-Dawley , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.
Subject(s)
Oxytocin/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Animals , Female , Humans , Kinetics , Oxytocin/metabolism , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Oxytocin/metabolism , Structure-Activity Relationship , Uterine Contraction/drug effectsABSTRACT
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.
Subject(s)
Indenes/chemical synthesis , Piperazines/chemical synthesis , Receptors, Oxytocin/antagonists & inhibitors , Administration, Oral , Animals , Antidiuretic Hormone Receptor Antagonists , Binding, Competitive , Biological Availability , CHO Cells , Calcium Signaling/drug effects , Cricetinae , Cricetulus , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Oxytocin/pharmacology , Piperazines/pharmacokinetics , Piperazines/pharmacology , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity Relationship , Uterine Contraction/drug effectsABSTRACT
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).
Subject(s)
Piperazines/chemical synthesis , Receptors, Oxytocin/antagonists & inhibitors , Administration, Oral , Animals , Antidiuretic Hormone Receptor Antagonists , Biological Availability , Crystallography, X-Ray , Dogs , Humans , Molecular Structure , Piperazines/pharmacokinetics , Piperazines/pharmacology , Radioligand Assay , Rats , Receptors, Oxytocin/chemistry , Serum Albumin/chemistry , Stereoisomerism , Structure-Activity Relationship , Uterine Contraction/drug effects , Vasotocin/analogs & derivatives , Vasotocin/pharmacologyABSTRACT
This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds.
Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptors, Oxytocin/antagonists & inhibitors , Humans , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described.