title: Design and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C-C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) Inhibitors.
abstract: A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schwehm
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
authors.forename: Barrie
authors.initials: B
authors.lastname: Kellam
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
authors.forename: Aimie E
authors.initials: AE
authors.lastname: Garces
authors.affiliation: Institute of Cell Signalling, Medical School, University of Nottingham , Nottingham, NG7 2UH, U.K.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hill
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Kindon
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.affiliation: Hitgen Ltd. , F7-10, Building B3, Tianfu Life Science Park, 88 South Kayuan Road, Chengdu, Sichuan, China 610041.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
authors.affiliation: GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: James E
authors.initials: JE
authors.lastname: Rowedder
authors.affiliation: Institute of Cell Signalling, Medical School, University of Nottingham , Nottingham, NG7 2UH, U.K.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Stoddart
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
authors.forename: Michael J
authors.identifier: 0000-0003-3046-137X
authors.initials: MJ
authors.lastname: Stocks
mesh_terms: D065100:CCR5 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D019713:Receptors, CCR5; D054852:Small Molecule Libraries; D058543:Class Ia Phosphatidylinositol 3-Kinase; D018819:Dipeptidyl Peptidase 4