2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists. 2. Synthesis, Chirality, and Pharmacokinetics

Abstract

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).

Cyclization-activated Prodrugs

“…The DKP scaffold is widely found in compounds of biological interest and could serve as a drug template with appropriate arrayed pharmacophores. To this point, studies showed that the replacement of a DKP cis-amide bound with structurally similar (z)-alkene units could provide DKP mimetics (16) as novel templates for creating drug-like structures [50][51][52][53][54]. Therefore, adequate linear dipeptide derivatives could act as prodrugs for DKP-based drugs.…”

The design of orally bioavailable 2, 5‐diketopiperazine oxytocin antagonists: from concept to clinical candidate for premature labor

“…5). 24 The X-ray crystal structure of 19 showed that the 3 and the 6 substituents are on the same face of the DKP ring, which is in a puckered conformation and confirmed the stereochemistry of the 3, 6, and 7 substituents as RRR.…”

“…4). 24 A four-carbon branched alkyl, isobutyl, or secbutyl was found to be optimal for potency at the 3-position, whereas increasing the size of the group to benzyl or decreasing it to methyl resulted in a reduction in potency. It was also confirmed that an aryl group was required at the 7-position as alkyl or cycloalkyl substituents at this position were at least 100-fold less potent than phenyl.…”

“…4) on this chiral system revealed that, alkylation of the ring N-atom or removal of the C2 carbonyl group resulted in a ten-fold drop in potency. 24 Additional SAR in this series 27 has been developed by the discovery of the importance of the exocyclic carbonyl for good potency. Although the carboxylic acid 45R has the same potency as the dimethylamide 40, the primary alcohol 46, prepared by reduction of the methyl ester, resulted in a significant loss in potency (410-fold) indicating that the carbonyl of these exocyclic functions is important for good activity (Fig.…”

“…However, although the 4 0 -F and 4 0 -NMe 2 derivatives had the best pharmacokinetic profile of these highly potent mono-4 0 -substituted phenyldiketopiperazines, they still had rather low bioavailability in the rat. 24 The question of how to improve the bioavailability of this template was addressed by analogy with a previous benzoxazine class of OT antagonists 28 where an aromatic fluoro substituent ) at 0.6 mgkg À1 5% DMSO/95% PEG400 formulation.…”