Efficacious, Orally Bioavailable Thrombin Inhibitors Based on 3-Aminopyridinone or 3-Aminopyrazinone Acetamide Peptidomimetic Templates

Abstract

We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

“…Pyrazinones have been incorporated into other drug candidate molecules such as inhibitors of human immunodeficiency virus-1 reverse transcriptase (Heeres et al, 2005), caspase-3 (Han et al, 2005), mast cell tryptase (Hopkins et al, 2004), and thrombin (Sanderson et al, 1998). Although metabolism of the majority of the pyrazinone-containing compounds remains unknown, metabolic activation of a series of thrombin inhibitors containing the 6-position substituted pyrazinone was published Singh et al, 2003;Subramanian et al, 2003;Deng et al, 2005;Lin et al, 2005).…”

Pharmacological Interruption of Acute Thrombus Formation with Minimal Hemorrhagic Complications by a Small Molecule Tissue Factor/Factor VIIa Inhibitor: Comparison to Factor Xa and Thrombin Inhibition in a Nonhuman Primate Thrombosis Model

“…The small molecule thrombin inhibitor 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)pyrazinone dihydrochloride (Sanderson et al, 1998) was synthesized in the Pfizer laboratories. Sanderson et al (1998) reported K i values for this compound of 0.8 nM against thrombin and 1800 nM against trypsin. The compound was dissolved to provide a stock solution with a concentration of 20 mg/ml in a combination of 10% ethanol, 10% PEG-400, and 80% sterile saline.…”

“…Throm-bin is also a potent platelet agonist, inducing platelet aggregation and possessing smooth muscle cell proliferative properties as well (Coughlin, 2000). Pharmacological attempts have been made at various points of potential intervention in the coagulation cascade, ranging from nonspecific inhibitors such as warfarin, unfractionated heparin, and low-molecular weight heparins, to specific inhibitors of factor Xa or direct acting thrombin inhibitors (Hara et al, 1995;Sanderson et al, 1998;Hauptmann and Sturzebecher, 1999;Pinto et al, 2001). Previous reports suggest that inhibitors of the TF/VIIa complex may prevent thrombosis with a lower bleeding risk than other types of coagulation inhibitors (Harker et al, 1996;Himber et al, 1997;Zoldhelyi et al, 2000).…”

“…The intent of the present study is to compare, in a nonhuman primate model of acute thrombus formation, the antithrombotic efficacy and propensity for bleeding diatheses of a small-molecule inhibitor of TF/VIIa (PHA-927F) to a selective, small-molecule inhibitor of factor Xa (Pinto et al, 2001) or a selective, small-molecule, direct-acting inhibitor of thrombin (Sanderson et al, 1998).…”

Exploring QSARs for inhibitory effect of a set of heterocyclic thrombin inhibitors by multilinear regression refined by artificial neural network and molecular docking simulations

“…These inhibitors possessed reactive functional groups such as aldehydes, activated ketones or boronic acids 8 . The non-peptide thrombin inhibitors with a heterocyclic core working as molecules with oral bioavailability gained special attention during the late 1990s decade [9][10][11][12][13] . Recently, Ries et al 14,15 have designed and developed orally active coagulation inhibitors with remarkably low molecular weight containing heterocyclic core structures as potent thrombin inhibitors in vitro.…”