Exploration of Potential Prodrugs of RWJ‐445167, an Oxyguanidine‐based Dual Inhibitor of Thrombin and Factor Xa

  title={Exploration of Potential Prodrugs of RWJ‐445167, an Oxyguanidine‐based Dual Inhibitor of Thrombin and Factor Xa},
  author={Bruce E. Maryanoff and David F. McComsey and Michael J. Costanzo and Stephen C. Yabut and Tianbao Lu and Mark R. Player and Edward C. Giardino and Bruce P. Damiano},
  journal={Chemical Biology \& Drug Design},
Compound 2 (RWJ‐445167; 3DP‐10017), a dual inhibitor of thrombin and factor Xa, was advanced into human clinical studies. However, its oral bioavailability in humans proved to be below acceptable limits. To address this issue, we explored a prodrug approach involving numerous guanidine derivatives. Prodrug candidates of classes A (carbamate derivatives), B (imidate derivatives), and C (alkyl and acyl derivatives), compounds 3–6, were synthesized and evaluated for anticoagulant activity at 2h… 

Transformation of a selective factor Xa inhibitor rivaroxaban into a dual factor Xa/thrombin inhibitor by modification of the morpholin-3-one moiety

Presented rationalization of dual activity provides a good starting point for “designing in” thrombin inhibitory activity to potent factor Xa inhibitor rivaroxaban.

Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif.

The Peptidylglycine α‐Amidating Monooxygenase (PAM): A Novel Prodrug Strategy for Amidoximes and N‐Hydroxyguanidines?

Previous prodrug strategies for amidoximes (and N-hydroxyguanidines) are now targeted to optimize metabolic and physicochemical stability, thereby further enhancing oral bioavailACHTUNGTRENNUNGability and their general applicability.

Applications of Fluorine in Medicinal Chemistry.

The effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography are provided, as well as new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds.

Mechanistic enhancement of the intestinal absorption of drugs containing the polar guanidino functionality

The barriers and challenges toward the oral absorption of guanidino-containing compounds are presented, an overview of the research that has been done so far is provided, and recent advances and future directions in the mechanistic enhancement of the intestinal absorption of drugs containing the polar guandino functionality are summarized.

5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally active dual thrombin and factor Xa inhibitor.

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The Medicinal Chemistry of Tuberculosis Chemotherapy

This chapter explores the medicinal chemistry efforts that gave rise to current frontline and second-line drugs in global use today and attempts to comprehensively summarize ongoing discovery and lead optimization programs being conducted in both the private and the public sector.

Emerging fluorination methods in organic chemistry relevant for life science application

Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach

The concept of prodrug design can no longer be viewed as merely a chemical modification to solve problems associated with parent compounds, rather, it opens promising opportunities for precise and efficient drug delivery, as well as enhancement of treatment options and therapeutic efficacy.



Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability.

Structure-based design of novel potent nonpeptide thrombin inhibitors.

A new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold is designed and the double-prodrug 31, which showed strong oral activity in different animal species, was chosen for clinical development.

The race to an orally active Factor Xa inhibitor: recent advances.

This review focuses on recent advances in the chemistry of drug design and lead optimization of orally bioavailable fXa inhibitors, which are anticipated to change the landscape of thrombosis therapy.

Oxyguanidines: application to non-peptidic phenyl-based thrombin inhibitors.

In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1' subsite and its implications to structure-based drug design.

Diverse heterocycle-activated ketones based on the d-Phe-Pro-Arg, and related thrombin active-site recognition motifs, as candidate inhibitors proved to be potent anticoagulant/antithrombotic agents in vivo on intravenous administration, whereas the benzothiazole carboxylate of 4 exhibited significantly diminished cardiovascular side effects, and benzoth Diazolecarboxylic acid 4 had the best profile with respect to therapeutic index.

Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis.

In vitro evaluation and crystallographic analysis of a new class of selective, non-amide-based thrombin inhibitors.

Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A.

  • B. MaryanoffX. Qiu A. Liu
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1993
The macrocyclic peptide cyclotheonamide A (CtA), isolated from the marine sponge Theonella sp., represents an unusual class of serine protease inhibitor. A complex of this inhibitor with human

Dual inhibitors of the blood coagulation enzymes.

The emphasis of this review will be placed on dual inhibitors of thrombin/factor Xa and factor Xa/factor VIIa, potentially, new anticoagulant drugs with improved properties.