title: Design and synthesis of conformationally restricted inhibitors of active thrombin activatable fibrinolysis inhibitor (TAFIa).
abstract: A series of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid derivatives designed as inhibitors of TAFIa has been prepared via a common hydrogenation-alkylation sequence starting from the appropriate benzimidazole and imidazopyridine system. We present a successful design strategy using a conformational restriction approach resulting in potent and selective inhibitors of TAFIa. The X-ray structure of compound 5 in complex with a H333Y/H335Q double mutant TAFI indicate that the conformational restriction is responsible for the observed potency increase.
authors.affiliation: Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Brink
authors.affiliation: Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Dahlén
authors.affiliation: Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden. Electronic address: magnus.polla@astrazeneca.com.
authors.forename: Magnus
authors.initials: M
authors.lastname: Polla
authors.affiliation: Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
authors.forename: Tor
authors.initials: T
authors.lastname: Svensson
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011725:Pyridines; D025901:Carboxypeptidase B2
keywords: AstraZeneca; Carboxypeptidase U; Conformational restriction; Imidazole; Rigidification; TAFIa