The last five years have seen an explosion of research into inhibitors of Factor Xa as potential antithrombotic agents. Aventis Pharma was a participant in this effort and its two founder companies have substantially contributed to the discovery of new inhibitors over the years. This review traces the systematic development of the former Rhone-Poulenc Rorer factor Xa program from conception to the realization of potent, orally bioavailable inhibitors with exquisite selectivity against other serine proteases. The work on beta-aminoesters described in Part 1 culminates in the development of FXV673 (Ki = 0.5 nM), an effective anticoagulant for acute indications. Part 2.2 details the de novo design of the pyrrolidinone series of inhibitors (RPR120844), within which a group of efficacious i.v. agents were identified (e.g. RPR130737, Ki = 2 nM). The first active and bioavailable benzamidine isostere i.e. the 1-aminoisoquinoline (RPR208815, Ki = 22 nM) was discovered on the pyrrolidinone scaffold (Part 2.3). Ultimately a variety of benzamidine mimics were explored and incorporated into the ketopiperazine series; the 6-substituted aminoquinazolines were found to be the most potent (Part 3). The azaindole, as represented by RPR200443 (Ki = 4 nM), stands out as imparting favorable pharmacokinetic properties to the sulfonamido-ketopiperazines.

01 Dec 1999·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Pharmacodynamic Activity and Antithrombotic Efficacy of RPR120844, a Novel Inhibitor of Coagulation Factor Xa

Q4 · MEDICINE

Article

Author: Ewing, W. Richard ; Morgan, Suzanne R. ; Dunwiddie, Christopher T. ; Brown, Karen ; Spada, Alfred P. ; Chu, Valeria ; Pauls, Henry ; Leadley, Robert J. Jr. ; Heran, Christopher ; Perrone, Mark H. ; Bentley, Ross ; Bostwick, Jeffrey S. ; Moxey, Phillip ; Kasiewski, Charles J.

These studies were designed to examine the pharmacodynamic profile and antithrombotic efficacy of RPR120844, a competitive inhibitor of coagulation factor Xa, with a K(i) of 7 nM against human factor Xa. In vitro, RPR120844 doubled activated partial thromboplastin time (APTT) at concentrations of 1.54, 1.48, and 0.74 microM in plasma obtained from humans, dogs, and rats, respectively. Intravenous bolus administration of RPR 120844 at 0.3, 1, and 3 mg/kg to rats resulted in maximal increases in APTT of 1.8-, 2.6-, and 8.4-fold over baseline, respectively. The effect on prothrombin time (PT) was less pronounced, resulting in a 4.4-fold increase at 3 mg/kg. These effects were rapidly reversible; APTT and PT returned to control values by 30 min after dosing. Intragastric administration to rats at 50, 100, and 200 mg/kg resulted in modest increases in APTT and PT of 1.5- and 1.3-fold over baseline at the highest dose. Plasma levels were estimated by anti-Xa activity by using an amidolytic, chromogenic assay. Plasma levels were 0.65, 1.29, and 2.45 microM at 30 min after dosing at 50, 100, and 200 mg/kg, respectively. Intravenous administration to dogs at 0.1 and 0.3 mg/kg produced maximal increases in APTT of 1.7- and 2.4-fold over baseline, respectively. Intragastric administration to dogs at 50 mg/kg resulted in maximal increases in APTT and PT of 1.7- and 1.1-fold over baseline, with peak plasma levels of 3.9 microM observed at 15 min after dosing. In a rat model of FeCl2-induced carotid artery thrombosis, RPR120844 (3 mg/kg, i.v. bolus + 300 microg/kg/min constant infusion; n = 4) significantly increased time-to-occlusion from 18+/-1 min (vehicle, n = 4) to 60 min (maximal observation time) and reduced thrombus mass from 5.5 +/- 0.2 mg (vehicle) to 1.4 +/- 0.2 mg. These results indicate that RPR120844 is a potent, selective inhibitor of Xa that exhibits oral activity and is efficacious in a standard model of arterial thrombosis.

01 Sep 1999·Journal of Medicinal ChemistryQ1 · MEDICINE

Sulfonamidopyrrolidinone Factor Xa Inhibitors: Potency and Selectivity Enhancements via P-1 and P-4 Optimization

Q1 · MEDICINE

Article

Author: Brown, Karen D. ; Cheney, Daniel L. ; Morris, Robert L. ; Mason, Helen J. ; Morgan, Suzanne R. ; Green, Daniel M. ; Dunwiddie, Christopher T. ; Leadley, Robert J. ; Bentley, Ross G. ; Ewing, William R. ; Dankulich, William P. ; Colussi, Dennis J. ; Heran, Christopher L. ; Choi-Sledeski, Yong Mi ; Spada, Alfred P. ; Guilloteau, Jean-Pierre ; Pauls, Henry W. ; Chu, Valeria ; Maignan, Sebastien ; Becker, Michael R. ; Manetta, Vincent E. ; McGarry, Daniel G. ; Davis, Roderick S.

Sulfonamidopyrrolidinones were previously disclosed as a selective class of factor Xa (fXa) inhibitors, culminating in the identification of RPR120844 as a potent member with efficacy in vivo. Recognizing the usefulness of the central pyrrolidinone template for the presentation of ligands to the S-1 and S-4 subsites of fXa, studies to optimize the P-1 and P-4 groups were initiated. Sulfonamidopyrrolidinones containing 4-hydroxy- and 4-aminobenzamidines were discovered to be effective inhibitors of fXa. X-ray crystallographic experiments in trypsin and molecular modeling studies suggest that our inhibitors bind by insertion of the 4-hydroxybenzamidine moiety into the S-1 subsite of the fXa active site. Of the P-4 groups examined, the pyridylthienyl sulfonamides were found to confer excellent potency and selectivity especially in combination with 4-hydroxybenzamidine. Compound 20b (RPR130737) was shown to be a potent fXa inhibitor (K(i) = 2 nM) with selectivity against structurally related serine proteinases (>1000 times). Preliminary biological evaluation demonstrates the effectiveness of this inhibitor in common assays of thrombosis in vitro (e.g. activated partial thromboplastin time) and in vivo (e.g. rat FeCl(2)-induced carotid artery thrombosis model).

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 1	US	Aventis SA	-

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