Structure-Based Design of Novel Guanidine/Benzamidine Mimics: Potent and Orally Bioavailable Factor Xa Inhibitors as Novel Anticoagulants
Citations Over TimeTop 13% of 2003 papers
Abstract
As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.
Related Papers
- → Inhibition of serine proteinases by benzamidine derivatives(1977)3 cited
- → Thrombin Inhibition by Novel Benzamidine Derivatives: A Free-Energy Perturbation Study(2002)9 cited
- → The Inactivation of Human C1 by Benzamidine and Pyridinium Sulfonylfluorides(1974)7 cited
- Effectiveness of Sepharose-bound trypsin versus liquid-phase trypsin plus benzamidine for activation of inactive renin in human plasma.(1987)
- → Inhibition of activated protein C by benzamidine derivatives(1993)1 cited