title: Sulfonamidopyrrolidinone factor Xa inhibitors: potency and selectivity enhancements via P-1 and P-4 optimization.
abstract: 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).
authors.affiliation: Departments of Cardiovascular Drug Discovery and New Leads Generation, Rhône-Poulenc Rorer, 500 Arcola Road, Collegeville, Pennsylvania 19426-0107, USA.
authors.forename: Y M
authors.initials: YM
authors.lastname: Choi-Sledeski
authors.forename: D G
authors.initials: DG
authors.lastname: McGarry
authors.forename: D M
authors.initials: DM
authors.lastname: Green
authors.forename: H J
authors.initials: HJ
authors.lastname: Mason
authors.forename: M R
authors.initials: MR
authors.lastname: Becker
authors.forename: R S
authors.initials: RS
authors.lastname: Davis
authors.forename: W R
authors.initials: WR
authors.lastname: Ewing
authors.forename: W P
authors.initials: WP
authors.lastname: Dankulich
authors.forename: V E
authors.initials: VE
authors.lastname: Manetta
authors.forename: R L
authors.initials: RL
authors.lastname: Morris
authors.forename: A P
authors.initials: AP
authors.lastname: Spada
authors.forename: D L
authors.initials: DL
authors.lastname: Cheney
authors.forename: K D
authors.initials: KD
authors.lastname: Brown
authors.forename: D J
authors.initials: DJ
authors.lastname: Colussi
authors.forename: V
authors.initials: V
authors.lastname: Chu
authors.forename: C L
authors.initials: CL
authors.lastname: Heran
authors.forename: S R
authors.initials: SR
authors.lastname: Morgan
authors.forename: R G
authors.initials: RG
authors.lastname: Bentley
authors.forename: R J
authors.initials: RJ
authors.lastname: Leadley
authors.forename: S
authors.initials: S
authors.lastname: Maignan
authors.forename: J P
authors.initials: JP
authors.lastname: Guilloteau
authors.forename: C T
authors.initials: CT
authors.lastname: Dunwiddie
authors.forename: H W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D000578:Amidines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011760:Pyrrolidinones; C121695:RPR 130737; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D013450:Sulfones