Thiophene-Anthranilamides as Highly Potent and Orally Available Factor Xa Inhibitors
- 31 May 2007
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 50 (13), 2967-2980
- https://doi.org/10.1021/jm070125f
Abstract
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.Keywords
This publication has 23 references indexed in Scilit:
- Substituted thiophene-anthranilamides as potent inhibitors of human factor XaBioorganic & Medicinal Chemistry, 2007
- Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): An Oral, Direct Factor Xa InhibitorJournal of Medicinal Chemistry, 2005
- Design, synthesis, and biological activity of non-amidine factor Xa inhibitors containing pyridine N-oxide and 2-carbamoylthiazole unitsBioorganic & Medicinal Chemistry, 2004
- Synthesis and Conformational Analysis of a Non-Amidine Factor Xa Inhibitor That Incorporates 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine as S4 Binding ElementJournal of Medicinal Chemistry, 2004
- Visions & Reflections Factor Xa - a promising target for drug developmentCellular and Molecular Life Sciences, 2002
- Preparation, Characterization, and the Crystal Structure of the Inhibitor ZK-807834 (CI-1031) Complexed with Factor Xa,Biochemistry, 2000
- Synthetic Inhibitors of Thrombin and Factor Xa: From Bench to BedsideThrombosis Research, 1999
- Potent Noncovalent Thrombin Inhibitors That Utilize the Unique Amino Acid d-Dicyclohexylalanine in the P3 Position. Implications on Oral Bioavailability and Antithrombotic EfficacyJournal of Medicinal Chemistry, 1997
- Direct thrombin inhibitors in cardiovascular medicine.Circulation, 1994
- A new sensitive and highly specific chromogenic peptide substrate for Factor XaThrombosis Research, 1977