Alfred P. Spada

Potent quinoxaline-Based inhibitors of PDGF receptor tyrosine kinase activity. Part 2: the synthesis and biological activities of RPR127963 an orally bioavailable inhibitor

RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1-5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.

Optimization of the β-aminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent in vivo anticoagulant activity

Further optimization of the beta-aminoester class of factor Xa (fXa) inhibitors is described culminating in the identification of 9c (FXV673), a potent and selective factor Xa inhibitor with excellent in vivo anticoagulant activity. An X-ray structure of FXV673 bound to human fXa is also presented. Based on its selectivity, potent in vivo activity and favorable pre-clinical safety profile, FXV673 was selected for further development and is currently undergoing clinical trials.

Potent quinoxaline-Based inhibitors of PDGF receptor tyrosine kinase activity. Part 1: SAR Exploration and Effective Bioisosteric Replacement of a phenyl substituent

Novel substituted 2-anilino- and 2-cycloalkylaminoquinoxalines have been found to be useful and selective inhibitors of PDGF-R autophosphorylation. Replacement of an anilino-substituent with substituted cyclohexylamino- or norbornylamino substituents led to significant improvements in the pharmacokinetic profile of these analogues.

Nonbenzamidine Compounds as Selective Factor Xa Inhibitors

Nonbenzamidine compounds (imidazole, pyridine, pyrimidine, and thiazole derivatives) as selective serine protease factor Xa inhibitors are discussed.

Optimization of the β-Aminoester class of factor Xa inhibitors. part 1: P4 and side-Chain modifications for improved In vitro potency

A systematic modification of the C(3) side-chain of the beta-aminoester class of factor Xa inhibitors and a survey of P(4) variations is described. These changes have resulted in the identification of sub-nanomolar inhibitors with improved selectivity versus related proteases. Coagulation parameters (i.e., APTT doubling concentrations) are also improved.

Benzimidazoles and isosteric compounds as potent and selective factor Xa inhibitors

Benzimidazoles and their isosteric compounds as factor Xa inhibitors are discussed.