the design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 10; no. 14; pp. 1567 - 1570
• Main Authors: Hayler, Judy, Kane, Peter D, LeGrand, Darren, Lugrin, Florence, Menear, Keith, Price, Richard, Allen, Mark, Cockcroft, Xiaoling, Ambler, John, Butler, Keith, Dunnet, Karren, Mitchelson, Andrew, Talbot, Mark, Tweed, Morris, Wills, Nicholas
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 17.07.2000; Elsevier
• Subjects: Administration, Oral; Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - chemistry; Alanine - pharmacokinetics; Animals; Antithrombins - chemical synthesis; Antithrombins - chemistry; Antithrombins - pharmacokinetics; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Chymotrypsin - antagonists & inhibitors; Drug Design; Fibrinolysin - antagonists & inhibitors; Kinetics; Medical sciences; Molecular Conformation; Molecular Structure; Partial Thromboplastin Time; Pharmacology. Drug treatments; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Thrombosis - drug therapy; Trypsin - metabolism; Rat; Cardiovascular disease; Non peptide compound; Thrombin; Physicochemical properties activity relationship; Morpholine derivatives; Vascular disease; Structure activity relation; Piperidine derivatives; Bicyclic compound; Aromatic compound; Chemical synthesis; Sulfur nitrogen heterocycle; Serine endopeptidases; Enzyme; Aminoamide; Rodentia; Oral administration; Enzyme inhibitor; Quinoline derivatives; Bioavailability; Benzothiazole derivatives; In vitro; Thrombosis; Peptidases; α-Aminoacid; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Hydrolases; Fluorine Organic compounds; Piperazine derivatives; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)00283-3

The further optimisation of the novel lead compound CGH752 (Fig. 1) is described. By introducing various substituents into the 6-position of the 3,3-dimethyltetrahydroquinoline (DMTHQS) ring we have been able to favourably affect the in vitro and in vivo activity, and the pharmacokinetics of such compounds. One of the inhibitors synthesised (CGH1484) is bioavailable and shows efficacy in animal models of thrombosis.