Discovery of an Orally Efficacious Inhibitor of Coagulation Factor Xa Which Incorporates a Neutral P₁Ligand

Abstract

The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…188 The potency was improved by almost 25-fold. Further optimization of the sulfonamide moiety resulted in 153 (fXa K i 5 1.1 nM).…”

Synthesis and innate immunosuppressive effect of 1,2-cyclopentanediol derivatives

“…After oxidation of 5, HornereEmmons reaction with ethyl diethylphosphorylmethanesulphonate [12] gave 41. Conversion of 41 into the tetrabutylammonium salt and chlorination produced the sulfonyl chloride 42 [13]. Treatment of 42 with methylamine afforded a methylsulfonamide, which was deprotected under acidic conditions to yield 43.…”

Kation‐π‐Wechselwirkungen im aktiven Zentrum von Faktor Xa: drastische Verstärkung durch stufenweise N‐Alkylierung von Ammoniumionen

“…B. einem Phenylamidiniumrest, besetzt, der in protonierter Form Ionenpaar-Wechselwirkungen mit der Seitenkette von Asp189 am Boden der S1-Tasche eingeht (Abbildung 1). In neueren Untersuchungen [3] wurden neutrale, bei oraler Verabreichung besser bioverfügbare Chloraryl-oder Chlorheteroarylsubstituenten als S1-Vektoren verwendet, die eine nahezu orthogonale dipolare C-Cl···C-O(H)-Wechselwirkung [4] mit der ebenfalls am Boden der Tasche befindlichen Seitenkette von Tyr228 eingehen. Die S4-Tasche bildet einen aromatischen Kasten, der von den Trp215-, Tyr99-und Phe174-Seitenketten begrenzt wird.…”