Chlorothiophenecarboxamides as P1 surrogates of inhibitors of blood coagulation factor Xa

Oral, Direct Thrombin and Factor Xa Inhibitors: The Replacement for Warfarin, Leeches, and Pig Intestines?

“…The morpholinone carbonyl group of the P4 residue leads to a vertical twisting of the morpholinone ring relative to the arene and polarizes the ring CH 2 group above Trp215, which reinforces the CH 2 ···p interaction. [42] The pattern of P1 and P4 residues present in rivaroxaban proved to be particularly efficient and was also adopted in other structures such as 35 [52] and 50.…”

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

“…[49c] Otamixaban (33) [50] von Aventis befindet sich in Phase III der klinischen [42] Das bei Rivaroxaban vorliegende Kombinationsmuster aus P1-und P4-Rest erwies sich als besonders effizient und wurde auch bei anderen Grundkörpern wie 35 [52] und 50 adaptiert. Razaxaban (37; Schema 14) war in Phase II der klinischen Entwicklung.…”

The Discovery of (2R,4R)‐N‐(4‐chlorophenyl)‐N‐ (2‐fluoro‐4‐(2‐oxopyridin‐1(2H)‐yl)phenyl)‐4‐methoxypyrrolidine‐1,2‐dicarboxamide (PD 0348292), an Orally Efficacious Factor Xa Inhibitor

“…The S4‐binding pocket of the FXa active site is described as an aromatic box because of the three aromatic amino acid side chains (Phe178, Trp215 and Tyr99) that form favourable binding interactions with either neutral or positively charged aromatic ligands (27–40). Reports from the literature showed that substituted heterocycles (imidazole, pyridines and pyrazoles) can be used as the P4 pharmacophore because of their aromatic nature and dispersed partial positive charge (16,27,37–40).…”

“…Reports from the literature showed that substituted heterocycles (imidazole, pyridines and pyrazoles) can be used as the P4 pharmacophore because of their aromatic nature and dispersed partial positive charge (16,27,37–40). It was also apparent that this binding pocket accommodates a wider variety of binding elements as inhibitors possessing non‐aromatic moieties like lactams, amides, cyclic amines and pyridones have been reported (14,27,31–34). Accordingly, the terminal phenylsulphone group of the P4 side chain was replaced with other groups in an attempt to retain potent, low‐molecular weight FXa inhibitors with better PK properties.…”

“…A subsequent crystal structure showed FXa complexed with a piperazinone‐based inhibitor that incorporated a neutral chlorothiophene group bound in the S1 pocket and a weakly basic azaindole group filling the S4 pocket (25,26). These results opened the door to the identification and design of new templates utilizing neutral P1 side chains as phenylamidine replacements in the discovery of FXa inhibitors (27–33). The results of these efforts have been highlighted by recent reports describing Bayer’s orally active FXa inhibitor rivaroxaban (Figure 1; 34).…”