Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization

Deng, James Z.; McMasters, Daniel R.; Rabbat, Philippe M. A.; Williams, Peter; Coburn, Craig A.; Yan, Yong-Bin; Kuo, Lawrence C.; Lewis, Sidney D.; Lucas, Bobby J.; Krueger, Julie A.; Strulovici, Berta; Vacca, Joseph P.; Lyle, Terry A.; Burgey, Christopher S.

doi:10.1016/j.bmcl.2005.07.022

Cited by 43 publications

(15 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[18] The same tendency was described for an additional series of dual thrombin and fXa inhibitors containing an oxazolopyridine core [19] and for nonpeptidic fXa inhibitors, which possess a thienopyridine N-oxide group as P3/P4 segment. [20] These results support the hypothesis that the reinforced interactions of the P3 2-pyridine-N-oxide group with Trp 215 contributes to affinity, because both thrombin and fXa contain Trp 215, whereas the other residues surrounding the aryl binding pocket are different in these proteases (Leu 99 and Ile 174 in thrombin, Tyr 99 and Phe 174 in fXa).…”

Section: Discussionmentioning

confidence: 83%

Highly Potent and Selective Substrate Analogue Factor Xa Inhibitors Containing D‐Homophenylalanine Analogues as P3 Residue: Part 2

et al. 2007

View full text Add to dashboard Cite

A series of highly potent substrate-analogue factor Xa inhibitors containing D-homophenylalanine analogues as the P3 residue has been identified by systematic optimization of a previously described inhibitor structure. An initial lead, benzylsulfonyl-D-hPhe-Gly-4-amidinobenzylamide (3), inhibits fXa with an inhibition constant of 6.0 nM. Most modifications of the P2 amino acid and P4 benzylsulfonyl group did not improve the affinity and selectivity of the compounds as fXa inhibitors. In contrast, further variation at the P3 position led to inhibitors with significantly enhanced potency and selectivity. Inhibitor 27, benzylsulfonyl-D-homo-2-pyridylalanyl(N-oxide)-Gly-4-amidinobenzylamide, inhibits fXa with a K(i) value of 0.32 nM. The inhibitor has strong anticoagulant activity in plasma and doubles the activated partial thromboplastin time and prothrombin time at concentrations of 280 nM and 170 nM, respectively. Compound 27 inhibits the prothrombinase complex with an IC(50) value of 5 nM and is approximately 50 times more potent than the reference inhibitor DX-9065a in this assay.

show abstract

Section: Discussionmentioning

confidence: 83%

Highly Potent and Selective Substrate Analogue Factor Xa Inhibitors Containing D‐Homophenylalanine Analogues as P3 Residue: Part 2

et al. 2007

View full text Add to dashboard Cite

show abstract

“…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). Of these thrombin inhibitors, a 3-amino-6-chloro-pyrazinone analog underwent extensive bioactivation in BDC rats after intravenous administration, leading to formation of a number of pyrazinone ring oxidation metabolites, such as the ring-opened metabolite and rearranged products, presumably via a pyrazinone epoxide intermediate (Subramanian et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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

Zhuo

Hartz²,

Bronson³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

(S)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)-phenylamino)pyrazin-2(1H)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0-7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.

show abstract

“…9), combines high potency (K i = 0.40 nM), excellent pharmacokinetic properties (F = 55%; t 1/2 : 14 h in dogs) and complete efficacy in an in vivo rat thrombosis model [150]. Chances for further development may also originate from a new oxazolpyridine series [151]. The dual thrombin/factor Xa inhibitor 33 ( Fig.…”

mentioning

confidence: 98%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.

show abstract

Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization

Cited by 43 publications

References 13 publications

Highly Potent and Selective Substrate Analogue Factor Xa Inhibitors Containing D‐Homophenylalanine Analogues as P3 Residue: Part 2

Highly Potent and Selective Substrate Analogue Factor Xa Inhibitors Containing D‐Homophenylalanine Analogues as P3 Residue: Part 2

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

Direct thrombin inhibitors – a survey of recent developments

Contact Info

Product

Resources

About