2,5-Diketopiperazines as potent and selective oxytocin antagonists 1: identification, stereochemistry and initial SAR

Wyatt, Paul G.; Allen, Michael J.; Borthwick, Alan D.; Davies, Dave E.; Exall, Anne M.; Hatley, Richard J. D.; Irving, Wendy R.; Livermore, David G.; Miller, Neil D.; Nerozzi, Fabrizio; Sollis, Steve L.; Szardenings, Anna Katrin

doi:10.1016/j.bmcl.2005.03.045

Cited by 66 publications

(32 citation statements)

References 9 publications

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“…This gave the 6-indanyl-3-isobuty isopropylamide 9 as the lead compound. In order to determine the preferred chirality of the exocyclic center at the 7-position and confirm the R chirality at the 3-and 6-position all the stereoisomers of the 6-indanyl-3-isobuty-7-phenyl-isopropylamide 9 were made using solution phase Ugi chemistry 23 (Scheme 1). The compounds with 3R,6R-stereochemistry in the DKP ring had the greatest potency with the 7R isomer 9a (pK i 5 8.4) tenfold more potent than the 7S isomer 9b.…”

Section: Template Discovery Synthesis and Initial Sarmentioning

confidence: 99%

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

Borthwick¹,

Liddle²

2011

Medicinal Research Reviews

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A short, efficient and highly stereoselective synthesis has been developed for a series of 6-indanyl-3-alkyl-7-aryl/heterocyclic-(3R, 6R, 7R)-2, 5-diketopiperazine amides that are potent and selective oxytocin (OT) antagonists. Property-based design using an estimate of human oral absorption enabled focus to be directed to those templates with the greatest chance of delivering high bioavailability in humans. This led to the 2', 4'-difluorophenyl dimethylamide 40, a highly potent (pK(i) =9.2) and selective OT antagonist (>1,000-fold selectivity vs. the human vasopressin receptors V1a, V2, and V1b) with good oral bioavailability (>50%) in the rat and dog. Increased solubility and an improved Cyp450 profile was achieved with a range of 2'-substituted 7-(1',3'-oxazol-4'-yl)-(3R,6R,7R)-2,5-diketopiperazine amides and branching at the α-carbon of the 3-butyl group led to a superior rat pharmacokinetic profile that resulted in the discovery of the 2'-methyl-1',3'-oxazol-4'-yl morpholine amide derivative 74 GSK221149A (Retosiban), which had the best oral exposure and bioavailability in the rat. Retosiban has sub-nanomolar affinity (K(i) =0.65 nM) for the oxytocin receptor with >1400-fold selectivity over the closely related vasopressin receptors. It has good solubility, low protein binding and has a good Cyp450 profile with no significant inhibition IC(50) >100 µM. Retosiban is >15-fold more potent at the human oxytocin receptor than atosiban (a marketed i.v, peptide OT antagonist) and it has been shown to be an effective tocolytic by i.v. and by oral administration in rats, and was selected for progression as a potential clinical candidate for preterm labor.

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Section: Template Discovery Synthesis and Initial Sarmentioning

confidence: 99%

“…The pool was generated using 24 amino esters 3 in a four-component Ugi reaction on solid phase 23 (Scheme 1). The reaction produced a mixture of stereoisomers at the exocyclic 7-position and therefore the pool contained 48 compounds.…”

Section: Template Discovery Synthesis and Initial Sarmentioning

confidence: 99%

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

Borthwick¹,

Liddle²

2011

Medicinal Research Reviews

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“…6 The bioactivities of these "regular DKPs" are well known and cover a variety of drug targets. 54,55 As one might expect, synthetic and medicinal chemists have generated very large numbers of nitrogen-based heterocyclic compounds, even though analyses of natural product sources show that oxygen-related heterocycles predominate. 56,57 On the topic of "underrepresented scaffolds," in 2009, chemists at UCBCelltech in the United Kingdom reported that they could identify approximately 25 000 small aromatic ring systems.…”

Section: Underprivileged Scaffoldsmentioning

confidence: 99%

Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs

Newman¹,

Cragg²

2014

Natural Products

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“…Significant progress has been made in identifying both peptide and nonpeptide oxytocin receptor antagonists (1,6,20,25,27,31,32,37). However, even though the newly developed peptide antagonists [such as barusiban and those described by Manning et al (20) and Stymiest et al (32)] are more potent and selective and serve as good research tools, their use in the clinic is still limited by having to be administered parenterally.…”

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confidence: 95%

“…It has been shown to reduce uterine contractions in vitro and in vivo and arrest preterm labor in pregnant women, resulting in a delay of delivery (13). While atosiban is efficacious at delaying delivery for 48 h, its use to prolong pregnancy beyond 48 h has been limited because it is only available for parenteral administration.Significant progress has been made in identifying both peptide and nonpeptide oxytocin receptor antagonists (1,6,20,25, 27,31,32,37). However, even though the newly developed peptide antagonists [such as barusiban and those described by Manning et al (20) and Stymiest et al (32)] are more potent and selective and serve as good research tools, their use in the clinic is still limited by having to be administered parenterally.…”

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confidence: 96%

Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

McCafferty¹,

Pullen²,

Wu³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Spontaneous and induced uterine contractions in the rat were found to be inhibited by a novel and selective oxytocin receptor antagonist GSK221149A (3R,6R)-3-Indan-2-yl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione. GSK221149A displayed nanomolar affinity (K(i) = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity (K(i) = 4.1 nM) and selectivity for native oxytocin receptors from rat and produced a functional, competitive block of oxytocin-induced contractions in isolated rat myometrial strips with a pA(2) value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID(50) = 0.27 +/- 0.60 mg/kg (corresponding plasma concentrations were 88 ng/ml). Oral administration of GSK221149A (5 mg/kg) was effective in inhibiting oxytocin-induced uterine contractions after single and multiple (4-day) dosing. Spontaneous uterine contractions in late-term pregnant rats (19-21 days gestation) were significantly reduced by intravenous administration of 0.3 mg/kg of GSK221149A. These results provide further evidence that selective oxytocin receptor antagonism may offer an effective treatment for preterm labor.

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2,5-Diketopiperazines as potent and selective oxytocin antagonists 1: identification, stereochemistry and initial SAR

Cited by 66 publications

References 9 publications

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

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

Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs

Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

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