Pancras C. Wong

Isoxazolines and isoxazoles as Factor Xa inhibitors

3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and evaluated for their in vitro and in vivo antithrombotic efficacy. They were compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and potency. They were also compared in an arterio-venous (A-V) shunt model of thrombosis.

ANTITHROMBOTIC ACTIONS OF SELECTIVE INHIBITORS OF BLOOD COAGULATION FACTOR Xa IN RAT MODELS OF THROMBOSIS

The antithrombotic actions of selective factor Xa (FXa) inhibitors, recombinant tick anticoagulant peptide (rTAP) and DX-9065a, were evaluated in experimental thrombosis models in anesthetized rats. In the first model, thrombosis was induced by exposing flowing blood to a silk thread anchored in an arteriovenous (AV) shunt. rTAP, DX-9065a and heparin, given as an iv infusion 1 hr before blood was circulated in the AV shunt, had ID50s of 0.007, 0.6 mumol/kg/hr and 16 U/kg/hr, respectively. In the model of venous thrombosis which was induced by hypotonic saline (0.225%) followed by 15-min stasis of abdominal vena cava, rTAP and heparin had ID50s of 0.007 mumol/kg/hr and 3.5 U/kg/hr, respectively. In both models, full inhibition of thrombus formation was achieved with FXa inhibition at doses which only modestly increased ex vivo plasma clotting time APTT (1.26 to 1.82 over the baseline). By contrast, the maximum antithrombotic effect of heparin was associated with high and significant APTT prolongation (> 5 fold over the baseline). Therefore, our study suggests that FXa inhibitors are effective agents in preventing thrombosis in both rat thrombosis models and may have therapeutic antithrombotic potential.

Synthesis and SAR of benzamidine factor Xa inhibitors containing a vicinally-substituted heterocyclic core.

The selective inhibition of coagulation factor Xa has emerged as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe highly potent benzamidine factor Xa inhibitors based on a vicinally-substituted heterocyclic core.

Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors

Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.

Preparation of meta-amidino-N,N-disubstituted anilines as potent inhibitors of coagulation factor Xa ☆

The serine protease factor Xa is a critical enzyme in the blood coagulation cascade. Recently, the inhibition of factor Xa has begun to emerge as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe a series of meta-amidino-N,N-disubstituted anilines as structurally simple and very potent inhibitors of factor Xa.

BALANCED ANGIOTENSIN II RECEPTOR ANTAGONISTS. III: THE EFFECTS OF SUBSTITUTION AT THE IMIDAZOLE 5-POSITION

Abstract We wish to report on a series of substituted methyl esters and amides of DMP 811, which bind to both the AT 1 and AT 2 receptor subtypes. Some of the esters bind well to both receptor subtypes in the subnanomolar range when the optimal acid isostere is present together with an ortho-fluorine substituent on the biphenylmethyl group.

Preparation of pyrrolidine and isoxazolidine benzamidines as potent inhibitors of coagulation factor Xa

The serine protease factor Xa is a critical enzyme in the blood coagulation cascade. Recently, the inhibition of factor Xa has begun to emerge as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe pyrrolidine and isoxazolidine benzamidines as novel and potent inhibitors of factor Xa.

Balanced angiotensin II receptor antagonists. I. The effects of biphenyl “ortho”-substitution on AT1/AT2 affinities

Abstract Biphenyl “ortho”-substitution of DuP 753-like AT1-selective angiotensin II receptor antagonists provides AT2 affinity. When combined with a sulfonylcarbamate as the acid isostere, balanced AT1/AT2 receptor antagonists were obtained. Some compounds exhibited nanomolar affinities for both receptors and good AT2/AT1 ratios; these compounds also produce potent and prolonged antihypertensive effects in renal hypertensive rats.

Nonpeptide angiotensin II receptor antagonists : the discovery of DMP 581 and DMP 811

Abstract A novel series of 4-alkylimidazoles have been prepared. Two of these compounds, DMP 581, 4-ethyl-2-propyl- 1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidiazole-5-carboxaldehyde, and DMP 811, 4-ethyl-2-propyl-1-[[2′-(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, possess among the highest oral antihypertensive potencies yet described for an angiotensin II antagonist. In addition, prodrugs of DMP 811 have been developed to further enhance the oral bioavailability of the parent diacid.

Imidazolinones as nonpeptide angiotensin II receptor antagonists

Abstract A series of biphenyl imidazolinones were synthesized as nonpeptide angiotensin II receptor antagonists. While those compounds with a tetrazole functionality were found to be AT 1 selective, those with a sulfonamide moiety showed affinities for both the AT 1 and the AT 2 sites. Representative compounds were very active in lowering blood pressure in conscious renal hypertensive rats following intravenous administration.