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Dan Larhammar - One of the best experts on this subject based on the ideXlab platform.

  • the vertebrate ancestral repertoire of visual opsins transducin alpha subunits and oxytocin Vasopressin Receptors was established by duplication of their shared genomic region in the two rounds of early vertebrate genome duplications
    BMC Evolutionary Biology, 2013
    Co-Authors: David Lagman, Jenny Widmark, Xesús M Abalo, Görel Sundström, Daniel Ocampo Daza, Dan Larhammar
    Abstract:

    Background Vertebrate color vision is dependent on four major color opsin subtypes: RH2 (green opsin), SWS1 (ultraviolet opsin), SWS2 (blue opsin), and LWS (red opsin). Together with the dim-light receptor rhodopsin (RH1), these form the family of vertebrate visual opsins. Vertebrate genomes contain many multi-membered gene families that can largely be explained by the two rounds of whole genome duplication (WGD) in the vertebrate ancestor (2R) followed by a third round in the teleost ancestor (3R). Related chromosome regions resulting from WGD or block duplications are said to form a paralogon. We describe here a paralogon containing the genes for visual opsins, the G-protein alpha subunit families for transducin (GNAT) and adenylyl cyclase inhibition (GNAI), the oxytocin and Vasopressin Receptors (OT/VP-R), and the L-type voltage-gated calcium channels (CACNA1-L).

  • the vertebrate ancestral repertoire of visual opsins transducin alpha subunits and oxytocin Vasopressin Receptors was established by duplication of their shared genomic region in the two rounds of early vertebrate genome duplications
    BMC Evolutionary Biology, 2013
    Co-Authors: David Lagman, Jenny Widmark, Xesús M Abalo, Görel Sundström, Daniel Ocampo Daza, Dan Larhammar
    Abstract:

    Vertebrate color vision is dependent on four major color opsin subtypes: RH2 (green opsin), SWS1 (ultraviolet opsin), SWS2 (blue opsin), and LWS (red opsin). Together with the dim-light receptor rhodopsin (RH1), these form the family of vertebrate visual opsins. Vertebrate genomes contain many multi-membered gene families that can largely be explained by the two rounds of whole genome duplication (WGD) in the vertebrate ancestor (2R) followed by a third round in the teleost ancestor (3R). Related chromosome regions resulting from WGD or block duplications are said to form a paralogon. We describe here a paralogon containing the genes for visual opsins, the G-protein alpha subunit families for transducin (GNAT) and adenylyl cyclase inhibition (GNAI), the oxytocin and Vasopressin Receptors (OT/VP-R), and the L-type voltage-gated calcium channels (CACNA1-L). Sequence-based phylogenies and analyses of conserved synteny show that the above-mentioned gene families, and many neighboring gene families, expanded in the early vertebrate WGDs. This allows us to deduce the following evolutionary scenario: The vertebrate ancestor had a chromosome containing the genes for two visual opsins, one GNAT, one GNAI, two OT/VP-Rs and one CACNA1-L gene. This chromosome was quadrupled in 2R. Subsequent gene losses resulted in a set of five visual opsin genes, three GNAT and GNAI genes, six OT/VP-R genes and four CACNA1-L genes. These regions were duplicated again in 3R resulting in additional teleost genes for some of the families. Major chromosomal rearrangements have taken place in the teleost genomes. By comparison with the corresponding chromosomal regions in the spotted gar, which diverged prior to 3R, we could time these rearrangements to post-3R. We present an extensive analysis of the paralogon housing the visual opsin, GNAT and GNAI, OT/VP-R, and CACNA1-L gene families. The combined data imply that the early vertebrate WGD events contributed to the evolution of vision and the other neuronal and neuroendocrine functions exerted by the proteins encoded by these gene families. In pouched lamprey all five visual opsin genes have previously been identified, suggesting that lampreys diverged from the jawed vertebrates after 2R.

Alan D Borthwick - One of the best experts on this subject based on the ideXlab platform.

  • the design of orally bioavailable 2 5 diketopiperazine oxytocin antagonists from concept to clinical candidate for premature labor
    ChemInform, 2011
    Co-Authors: Alan D Borthwick, John Liddle
    Abstract:

    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.

  • the design of orally bioavailable 2 5 diketopiperazine oxytocin antagonists from concept to clinical candidate for premature labor
    Medicinal Research Reviews, 2011
    Co-Authors: Alan D Borthwick, John Liddle
    Abstract:

    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 (pKi=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 (Ki=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 IC50>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.  © 2009 Wiley Periodicals, Inc. Med Res Rev 31:576-604, 2011

  • pyridyl 2 5 diketopiperazines as potent selective and orally bioavailable oxytocin antagonists synthesis pharmacokinetics and in vivo potency
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Alan D Borthwick, John Liddle, Anne M Exall, Christopher Charles Frederick Hamlett, Dave E Davies, Fabrizio Nerozzi, Deirdre Mary Bernadette Hickey, Andrew Mcmurtrie Mason, Ian E Smith, Simon Peace
    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 (pKi > 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 (pKi = 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 saf...

  • 2 5 diketopiperazines as potent selective and orally bioavailable oxytocin antagonists 2 synthesis chirality and pharmacokinetics
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Alan D Borthwick, Michael Allen, Anne M Exall, Dave E Davies, Livermore David, Steve L Sollis, Fabrizio Nerozzi, Marion J Perren, Shalia Shabbir, Patrick M Woollard
    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).

David Lagman - One of the best experts on this subject based on the ideXlab platform.

  • the vertebrate ancestral repertoire of visual opsins transducin alpha subunits and oxytocin Vasopressin Receptors was established by duplication of their shared genomic region in the two rounds of early vertebrate genome duplications
    BMC Evolutionary Biology, 2013
    Co-Authors: David Lagman, Jenny Widmark, Xesús M Abalo, Görel Sundström, Daniel Ocampo Daza, Dan Larhammar
    Abstract:

    Background Vertebrate color vision is dependent on four major color opsin subtypes: RH2 (green opsin), SWS1 (ultraviolet opsin), SWS2 (blue opsin), and LWS (red opsin). Together with the dim-light receptor rhodopsin (RH1), these form the family of vertebrate visual opsins. Vertebrate genomes contain many multi-membered gene families that can largely be explained by the two rounds of whole genome duplication (WGD) in the vertebrate ancestor (2R) followed by a third round in the teleost ancestor (3R). Related chromosome regions resulting from WGD or block duplications are said to form a paralogon. We describe here a paralogon containing the genes for visual opsins, the G-protein alpha subunit families for transducin (GNAT) and adenylyl cyclase inhibition (GNAI), the oxytocin and Vasopressin Receptors (OT/VP-R), and the L-type voltage-gated calcium channels (CACNA1-L).

  • the vertebrate ancestral repertoire of visual opsins transducin alpha subunits and oxytocin Vasopressin Receptors was established by duplication of their shared genomic region in the two rounds of early vertebrate genome duplications
    BMC Evolutionary Biology, 2013
    Co-Authors: David Lagman, Jenny Widmark, Xesús M Abalo, Görel Sundström, Daniel Ocampo Daza, Dan Larhammar
    Abstract:

    Vertebrate color vision is dependent on four major color opsin subtypes: RH2 (green opsin), SWS1 (ultraviolet opsin), SWS2 (blue opsin), and LWS (red opsin). Together with the dim-light receptor rhodopsin (RH1), these form the family of vertebrate visual opsins. Vertebrate genomes contain many multi-membered gene families that can largely be explained by the two rounds of whole genome duplication (WGD) in the vertebrate ancestor (2R) followed by a third round in the teleost ancestor (3R). Related chromosome regions resulting from WGD or block duplications are said to form a paralogon. We describe here a paralogon containing the genes for visual opsins, the G-protein alpha subunit families for transducin (GNAT) and adenylyl cyclase inhibition (GNAI), the oxytocin and Vasopressin Receptors (OT/VP-R), and the L-type voltage-gated calcium channels (CACNA1-L). Sequence-based phylogenies and analyses of conserved synteny show that the above-mentioned gene families, and many neighboring gene families, expanded in the early vertebrate WGDs. This allows us to deduce the following evolutionary scenario: The vertebrate ancestor had a chromosome containing the genes for two visual opsins, one GNAT, one GNAI, two OT/VP-Rs and one CACNA1-L gene. This chromosome was quadrupled in 2R. Subsequent gene losses resulted in a set of five visual opsin genes, three GNAT and GNAI genes, six OT/VP-R genes and four CACNA1-L genes. These regions were duplicated again in 3R resulting in additional teleost genes for some of the families. Major chromosomal rearrangements have taken place in the teleost genomes. By comparison with the corresponding chromosomal regions in the spotted gar, which diverged prior to 3R, we could time these rearrangements to post-3R. We present an extensive analysis of the paralogon housing the visual opsin, GNAT and GNAI, OT/VP-R, and CACNA1-L gene families. The combined data imply that the early vertebrate WGD events contributed to the evolution of vision and the other neuronal and neuroendocrine functions exerted by the proteins encoded by these gene families. In pouched lamprey all five visual opsin genes have previously been identified, suggesting that lampreys diverged from the jawed vertebrates after 2R.

Gilles Guillon - One of the best experts on this subject based on the ideXlab platform.

  • affinity and efficacy of selective agonists and antagonists for Vasopressin and oxytocin Receptors an easy guide to receptor pharmacology
    Progress in Brain Research, 2008
    Co-Authors: Bice Chini, Maurice Manning, Gilles Guillon
    Abstract:

    The development of "selective" drugs targeting oxytocin/Vasopressin Receptors has enormously progressed since the original synthesis of oxytocin more than 50 years ago. However, several factors still hamper the availability of a rich and complete range of selective agonists and antagonists acting at the different oxytocin/Vasopressin receptor subtypes, making the use of these drugs still a daunting task. In this paper we will briefly review the major problems encountered when dealing with oxytocin/Vasopressin selective ligands, proving few rules for their correct pharmacological use, in order to avoid common pitfalls. Finally, we will glimpse at new challenges, such us the discovery of coupling selective ligands, which foster the search for new classes of selective compounds.

  • mapping the binding site of arginine Vasopressin to v1a and v1b Vasopressin Receptors
    Molecular Endocrinology, 2007
    Co-Authors: Jordi Rodrigo, Gilles Guillon, Miguel Trueba, Thierry Durroux, Ana Pena, Brigitte Murat, Didier Rognan
    Abstract:

    Starting from the 2.8-A resolution x-ray structure of bovine rhodopsin, three-dimensional molecular models of the complexes between arginine Vasopressin and two receptor subtypes (V1a, V1b) have been built. Amino acid sequence alignment and docking studies suggest that four key residues (1.35, 2.65, 4.61, and 5.35) fine tune the binding of Vasopressin and related peptide agonists to both receptor subtypes. To validate these predictions, a series of single or double mutants were engineered at V1a and V1b receptor subtypes and tested for their binding and functional properties. Two negatively charged amino acids at positions 1.35 and 2.65 are key anchoring residues to the Arg8 residue of arginine Vasopressin. Moreover, two amino acids (V4.61 and P5.35) delineating a hydrophobic subsite at the human V1b receptor are responsible for the recognition of V1b selective peptide agonists. Last, one of the latter positions (5.35) is hypothesized to explain the pharmacological species differences between rat and huma...

  • 1 deamino 4 cyclohexylalanine arginine Vasopressin a potent and specific agonist for Vasopressin v1b Receptors
    Endocrinology, 2002
    Co-Authors: Sylvain Derick, Miriam Andres, Ling Ling Cheng, Mariejeanne Voirol, Stoytcho Stoev, M Giacomini, Hazel H Szeto, Ben M Mimoun, R Gaillard, Gilles Guillon
    Abstract:

    To date, there are no Vasopressin (VP) agonists that exhibit a high affinity and selectivity for the VP V1b receptor with respect to the V1a, V2, and oxytocin Receptors. In this study, we describe the synthesis and pharmacological properties of [1-deamino-4-cyclohexylalanine] arginine Vasopressin (d[Cha4]AVP). Binding experiments performed on various membrane preparations revealed that d[Cha4]AVP exhibits a nanomolar affinity for V1b Receptors from various mammalian species (rat, bovine, human). It exhibits high V1b/V1a and V1b/oxytocin selectivity for rat, human, and bovine Receptors. Furthermore, it exhibits high V1b/V2 specificity for both bovine and human Vasopressin Receptors. Functional studies performed on biological models that naturally express V1b Receptors indicate that d[Cha4]AVP is an agonist. Like VP, it stimulated basal and corticotropin-releasing factor-stimulated ACTH secretion and basal catecholamine release from rat anterior pituitary and bovine chromaffin cells, respectively. In vivo e...

  • pharmacological characterization of f 180 a selective human v1a Vasopressin receptor agonist of high affinity
    British Journal of Pharmacology, 2002
    Co-Authors: Miriam Andres, Miguel Trueba, Gilles Guillon
    Abstract:

    1. The pharmacological properties of F-180, a Vasopressin (VP) structural analogue, were determined on CHO cells expressing the different human Vasopressin and oxytocin (OT) receptor subtypes. Binding experiments revealed that F-180 exhibited a high affinity for the human V(1a) receptor subtype (K(i)=11 nM) and was selective for this receptor subtype. 2. Functional studies performed on CHO cells expressing human V(1a) Receptors indicate that similarly to AVP, F-180 can stimulate the accumulation of inositol phosphate. The activation constant (K(act)) for both F-180 and AVP was 1.7 nM. F-180 was also an agonist for the human V(2) and V(1b) receptor subtypes and an antagonist for the human OT receptor. 3. Since marked species pharmacological differences for Vasopressin Receptors have been described, we studied the properties of F-180 on various mammalian species. F-180 showed high affinity and good selectivity for human and bovine V(1a) Receptors, but weak affinity and non selective properties for rat V(1a) Receptors. 4. To assess the functional properties of F-180 on a native biological model, we performed studies on primary cultures of cells from bovine zona fasciculata (ZF). As AVP, F-180 stimulated inositol phosphate accumulation and cortisol secretion with similar efficiency. 5. In conclusion, we demonstrate that F-180 is the first selective V(1a) agonist described for human and bovine Vasopressin Receptors. Therefore F-180 can be used as a powerful pharmacological tool to characterize the actions of Vasopressin that are mediated by V(1a) receptor subtypes.

  • Vasopressin a potent autocrine paracrine regulator of mammal adrenal functions
    Endocrine Research, 1998
    Co-Authors: Gilles Guillon, Eric Grazzini, M. Andrez, Christophe Breton, M. Trueba, G. Boccara, Sylvain Derick, Lucie Chouinard, Serradeille C Gal, Nicole Gallopayet
    Abstract:

    The control of adrenal functions by locally secreted neuropeptides or neutotransmitters is of great physiological importance. Vasopressin (VP) is one of these autocrine/paracrine regulators. We demonstrated by RT-PCR and perifusion experiments that rat and human adrenal medulla expressed and released Vasopressin under basal conditions and under stimulation by acetylcholine. Intra-adrenal concentrations of VP may be sufficient to activate adrenal VP Receptors. In the cortex, only the V1a receptor subtype has been detected. It triggered both steroid secretion and cortical growth. In the medulla, both V1a and V1b receptor subtypes were expressed. V1b Receptors were mainly present on chromaffin cells and stimulated catecholamine secretion. The role of the V1a receptor remains unclear. Pathophysiological studies also revealed that human pheochromocytoma did not overexpress Vasopressin Receptors but might oversecrete Vasopressin causing high plasma VP concentrations and elevated blood pressure.

John Liddle - One of the best experts on this subject based on the ideXlab platform.

  • the design of orally bioavailable 2 5 diketopiperazine oxytocin antagonists from concept to clinical candidate for premature labor
    ChemInform, 2011
    Co-Authors: Alan D Borthwick, John Liddle
    Abstract:

    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.

  • the design of orally bioavailable 2 5 diketopiperazine oxytocin antagonists from concept to clinical candidate for premature labor
    Medicinal Research Reviews, 2011
    Co-Authors: Alan D Borthwick, John Liddle
    Abstract:

    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 (pKi=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 (Ki=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 IC50>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.  © 2009 Wiley Periodicals, Inc. Med Res Rev 31:576-604, 2011

  • pyridyl 2 5 diketopiperazines as potent selective and orally bioavailable oxytocin antagonists synthesis pharmacokinetics and in vivo potency
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Alan D Borthwick, John Liddle, Anne M Exall, Christopher Charles Frederick Hamlett, Dave E Davies, Fabrizio Nerozzi, Deirdre Mary Bernadette Hickey, Andrew Mcmurtrie Mason, Ian E Smith, Simon Peace
    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 (pKi > 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 (pKi = 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 saf...