Identification of potent and selective oxytocin antagonists. Part 2: further investigation of benzofuran derivatives

Wyatt, Paul G.; Allen, Michael J.; Chilcott, Josie; Gardner, C.; Livermore, David G.; Mordaunt, Jackie E.; Nerozzi, Fabrizio; Patel, Mamta; Perren, M.J.; Weingarten, Gordon G.; Shabbir, Shaila; Woollard, P.M.; Zhou, Ping

doi:10.1016/s0960-894x(02)00160-9

Cited by 46 publications

(24 citation statements)

References 10 publications

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“…In another study, the hOTR model was built with the bRho template [21]. In order to obtain relevant structure-activity relationships, we have now carried out QSAR calculations on the receptor-based alignment of 58 BZX hOTR antagonists (Tables 1 and 2, [22,23], compounds are provided in Supplementary Information in SMILES format), with the aims: (1) docking 57 non-peptide OT antagonists to the putative active site of the hOTR, determined earlier [20]; (2) characterization of the 58 receptor-ligand Table 1 Structures and measured pK i values of the OT antagonists (training set) ID R pK i imposed with the most active ligand, and docking calculations were performed to obtain the receptor-based alignment. The docking procedures were carried out with the AutoDock 3.05 Software [24] with the following parameters: the grid box (40 Â 40 Â 60 grid point, 0.375 Å grid point distance) was centred on the ligand; in the calculation of the electrostatic grid map, the distance-dependent dielectric constant of Mehler and Solmayer [25] was applied, for the van der Waals interaction the 12-6, and for the H-bond the 12-10 Lennard-Jones potential was utilized.…”

Section: Introductionmentioning

confidence: 99%

Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists

Jójárt

Márki

2007

Journal of Molecular Graphics and Modelling

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Section: Introductionmentioning

confidence: 99%

Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists

Jójárt

Márki

2007

Journal of Molecular Graphics and Modelling

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“…6). PK/PD comparisons of 40 with other OT antagonists: atosiban, our previous OT antagonist template 28 and Merck L-371257, in the rat uterine contractility model (Fig. 6) using the same OT challenge of 0.3 mg mL À1 throughout showed that 40 has the best efficacy in this species.…”

Section: In Vivo Potencymentioning

confidence: 91%

“…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.…”

Section: Pharmacokinetics and Property-based Designmentioning

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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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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“…Various structural modifications of this compound have been prepared in order to increase the affinity toward human OTRs [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…In the present work we have made an attempt to identify the key elements of the receptor-ligand interaction for 45 nonpeptide OTR BZX analogs taken from the literature [8,9] (Tables 1a-f). The problem was addressed by using molecular docking incorporating receptor flexibility with constrained simulated annealing (CSA) in order to generate binding hypotheses.…”

Section: Introductionmentioning

confidence: 99%

The 3D Structure of the Binding Pocket of the Human Oxytocin Receptor for Benzoxazine Antagonists, Determined by Molecular Docking, Scoring Functions and 3D-QSAR Methods

Jójárt

Martinek

Márki

2005

J Comput Aided Mol Des

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Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated deltaG(bind) and the pKi values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q2(CoMFA) = 0.653, q2(CoMSA) = 0.630 and r2(pred,CoMFA) = 0.852 , r2(pred,CoMSIA) = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

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Identification of potent and selective oxytocin antagonists. Part 2: further investigation of benzofuran derivatives

Cited by 46 publications

References 10 publications

Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists

Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists

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

The 3D Structure of the Binding Pocket of the Human Oxytocin Receptor for Benzoxazine Antagonists, Determined by Molecular Docking, Scoring Functions and 3D-QSAR Methods

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