The discovery of GSK221149A: A potent and selective oxytocin antagonist

Liddle, John; Allen, Michael J.; Borthwick, Alan D.; Brooks, David P.; Davies, D. E.; Edwards, Richard M.; Exall, Anne M.; Hamlett, Chris; Irving, Wendy R.; Mason, Andrew M.; McCafferty, Gerald P.; Nerozzi, Fabrizio; Peace, Simon; Philp, Joanne; Pollard, Derek; Pullen, Mark; Shabbir, Shaila; Sollis, Steve L.; Westfall, Timothy D.; Woollard, Pat M.; Wu, Chunchi; Hickey, Deirdre M. B.

doi:10.1016/j.bmcl.2007.11.008

Cited by 80 publications

(45 citation statements)

References 14 publications

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“…Although not common in existing compound libraries, MCR compounds are well represented among known small-molecule PPI inhibitors [16], [17], [18]. More importantly, MCR derived peptido-mimetic chemotypes allow us to design compound libraries that include chemical mimics of key amino acids important for molecular recognition [19].…”

Section: Resultsmentioning

confidence: 99%

Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists

et al. 2012

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Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure.

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Section: Resultsmentioning

confidence: 99%

Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists

et al. 2012

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“…Results from mutagenesis experiments and molecular modeling suggest a locus in transmembrane helix 7 of the oxytocin receptor that provides a high-affinity binding site for benzoxazine antagonists [15] . One of the members of diketopiperazines, compound GSK221149A ( 4 in Figure 2 ) ( showed nanomolar affinity for the oxytocin receptor and a more than 1000-fold selectivity over the closely related vasopressin V1a receptor [46,47] . GSK221149A is an orally bioavailable oxytocin antagonist.…”

Section: Nonpeptide Oxytocin Ligands 221 Nonpeptide Oxytocin Antagomentioning

confidence: 99%

Oxytocin receptor ligands: a survey of the patent literature

Gimpl¹

2008

Expert Opinion on Therapeutic Patents

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Background : Oxytocin is produced primarily in hypothalamic neurons and is secreted from the posterior pituitary gland into the circulation in response to stimuli such as suckling, parturition, or stress. Oxytocin functions as an essential component in milk ejection and is among the most potent uterotonic substances known. The oxytocin receptor system supports physiological processes associated with reproduction at several levels. Objective : To characterize and evaluate oxytocin receptor ligands for therapeutic applications. Methods : Analysis of oxytocin analogs and nonpeptide oxytocin receptor ligands, and major applications of these substances. Results/conclusion : Oxytocin receptor ligands, peptides, and nonpeptide molecules, with high specificity over the related vasopressin receptors, are currently available. These ligands are expected to show therapeutic utility for a vast range of applications, e.g., increasing lactation, improving in vitro inseminations, and inducing cardiomyogenesis; and also acting against preterm labor, breast cancer, an over-reactive immune system, osteoporosis, and autism-related disorders.

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“…Trifluoromethylfuran 3 is an agonist of the EP prostanoids [15]. The derivative 4 is an antagonist of oxytocin, a well-known agent for stimulating contractility in human myometrium that is widely used for the induction of labour [16]. Some derivatives of trifluoromethylfuran reveal also antibacterial [17] and antiparasite activity [18] (for example, compounds 5 and 6).…”

Section: Introductionmentioning

confidence: 99%