Synthesis of a Series of Potent and Orally Bioavailable Thrombin Inhibitors That Utilize 3,3-Disubstituted Propionic Acid Derivatives in the P3 Position

• Published in: Journal of medicinal chemistry Vol. 40; no. 22; pp. 3687 - 3693
• Main Authors: Tucker, Thomas J, Lumma, William C, Lewis, S. Dale, Gardell, Stephen J, Lucas, Bobby J, Sisko, Jack T, Lynch, Joseph J, Lyle, Elizabeth A, Baskin, Elizabeth P, Woltmann, Richard F, Appleby, Sandra D, Chen, I-Wu, Dancheck, Kimberley B, Naylor-Olsen, Adel M, Krueger, Julie A, Cooper, Carolyn M, Vacca, Joseph P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 24.10.1997
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Dogs; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology. Drug treatments; Propionates - chemical synthesis; Propionates - pharmacokinetics; Propionates - pharmacology; Rats; Spectrometry, Mass, Fast Atom Bombardment; Thrombin - antagonists & inhibitors; Cyclohexane derivatives; Rat; Cardiovascular disease; Non peptide compound; Thrombin; Anticoagulant; Vascular disease; Structure activity relation; Chemical synthesis; Dog; Human; Fissipedia; Carnivora; Serine endopeptidases; Enzyme; Aminoamide; Rodentia; Oral administration; Enzyme inhibitor; Bioavailability; In vitro; Thrombosis; Peptidases; In vivo; α-Aminoacid; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Hydrolases; Carboxamide; Pharmacokinetics; Primary amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970397q

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a,b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.