Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

Abstract

Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed.

Synthesis and evaluation of tripeptidic plasmin inhibitors with nitrile as warhead

“…The next attempt we tackled was to find the new non‐natural amino acids as the P1 residue for plasmin inhibitors having a nitrile moiety. The key interaction of rivaroxaban with the S1 pocket in FXa involves the five‐membered ring‐like chlorothiophene . There are, however, no reports on the non‐natural amino acid P1 residues for the plasmin inhibitors possessing a warhead.…”

“…These preferred residues were then successfully utilized for identifying peptidic and non‐peptidic inhibitors for the proteases as the charged P1 group . Of the various types of the trypsin‐like serine protease inhibitors investigated, rivaroxaban for factor Xa (FXa) was developed as a new inhibitor with a non‐basic chlorothiophene as the P1 moiety instead of a basic residue like Arg or Lys .…”

Designing Allosteric Regulators of Thrombin. Monosulfated Benzofuran Dimers Selectively Interact With Arg173 of Exosite 2 to Induce Inhibition

“…8-10 This strategy has also been exploited in the design of rivaroxaban, a non-amidine or guanidine based factor Xa inhibitor, approved for clinical use in the EU. 11 …”

Predicting subsite interactions of plasmin with substrates and inhibitors through computational docking analysis

“…The terminus of the O-picolyl-Tyr moiety was located in the pocket formed by Glu724, Ser760, Trp761, Leu775, and the S2 wall, hereinafter referred as "extra S2 pocket". This additional extra S2 pocket was composed mainly of hydrophobic residues and was located at the back side of the S2 site, and appears to correspond with the S4 site of factor Xa 22 . The octylamide moiety of YO-2 adopted an extended conformation and protruded from the area formed by Thr581, Met585, Phe587, Cys588, Cys604, Lys607, Tyr614, and Gln738 (Figure 5b).…”