P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold

Nantermet, Philippe G.; Burgey, Christopher S.; Robinson, Kyle A.; Pellicore, Janetta M.; Newton, Christina L.; Deng, James Z.; Selnick, Harold G.; Lewis, Sidney D.; Lucas, Bobby J.; Krueger, Julie A.; Miller‐Stein, Cynthia; White, Rebecca B.; Wong, Bradley K.; McMasters, Daniel R.; Wallace, Audrey A.; Lynch, Joseph J.; Yan, Yong-Bin; Chen, Zhongguo; Kuo, Lawrence C.; Gardell, Stephen J.; Shafer, Jules A.; Vacca, Joseph P.; Lyle, Terry A.

doi:10.1016/j.bmcl.2005.03.110

Cited by 21 publications

(10 citation statements)

References 15 publications

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“…In this regard, inhibitors of both thrombin and factor Xa have attracted considerable recent attention. Nantermet et al [179], demonstrated during their experiments that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core was more resistant toward oxidative metabolism, it also defeated the metabolic liability associated with the pyrazinones.…”

Section: Other Applicationsmentioning

confidence: 98%

Peptidomimetics and their Applications in Antifungal Drug Design

Moradi¹,

Soltani²,

Ansari³

et al. 2009

AIAMC

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The antimicrobial peptides represent diverse structures for drug design. They have been looked at as potential sources of new antimicrobial drugs to combat the increasing threat posed by multiple drug resistant microorganisms. Unfortunately, peptides themselves provide inferior drug candidates because of their low oral bioavailability, potential immunogenicity, poor in vivo metabolic stability, high molecular weight and most importantly being exposed by enzymes like proteases. Recent efforts to resolve disadvantageous peptide characteristics, and thus generating practical pharmaceutical therapies, have focused on the creation of non-natural peptide mimetics. Peptidomimetic molecules may have reduced immunogenicity and improved bioavailability relative to peptide analogues. Also the artificial backbone makes most peptidomimetics resistant to degradative enzymes thus increasing the stability of peptidomimetic drugs in the body. In this article, after introducing antifungal peptides, benefits and limitations, and peptidomemetics usage are discussed and applications in drug discovery process and antifungal research will be presented.

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Section: Other Applicationsmentioning

confidence: 98%

Peptidomimetics and their Applications in Antifungal Drug Design

Moradi¹,

Soltani²,

Ansari³

et al. 2009

AIAMC

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“…Thus, the original pyrazinone core was replaced by pyridine N -oxide, which was shown to resist metabolic oxidation that plagued the pyrazinones. [76]…”

Section: Case Studies Of Heterocyclic N-oxide Drugs and Emerging Bmentioning

confidence: 99%

“…[76] Thus, oral administration of compound 57 showed peak plasma levels of 0.82 mM and a half-life of 1.5 hr, while peak plasma levels of 0.7 mM with t 1/2 of 1.3 hr were attained for compound 59 . All other analogues displayed inferior pharmacokinetics profiles.…”

Section: Case Studies Of Heterocyclic N-oxide Drugs and Emerging Bmentioning

confidence: 99%

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Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents

Mfuh¹,

Larionov

2015

CMC

135

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Heterocyclic N-oxides have emerged as potent compounds with anticancer, antibacterial, antihypertensive, antiparasitic, anti-HIV, anti-inflammatory, herbicidal, neuroprotective, and procognitive activities. The N-oxide motif has been successfully employed in a number of recent drug development projects. This review surveys the emergence of this scaffold in the mainstream medicinal chemistry with a focus on the discovery of the heterocyclic N-oxide drugs, N-oxide-specific mechanisms of action, drug-receptor interactions and synthetic avenues to these compounds. As the first review on this subject that covers the developments since 1950s to date, it is expected that it will inspire wider implementation of the heterocyclic N-oxide motif in the rational design of new medicinal agents.

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“…However, it was less resistant to oxidative metabolism. Researchers from Merck Research Laboratories found that 2-aminopyridine N-oxide in the P2 position confers reduced metabolic liability compared to that of pyrazinones (39).…”

Section: The Development Of Direct Thrombin Inhibitorsmentioning

confidence: 99%

Direct thrombin inhibitors: Patents 2002–2012 (Review)

Kong

Chen

Wang

et al. 2014

Molecular Medicine Reports

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Acute vascular diseases and other thromboses of the blood system constitute major health risks in developing countries. Thrombin plays a central role in blood coagulation, which is a crucial process involved in thrombosis. Direct thrombin inhibitors (DTIs) such as argatroban, dabigatran, dabigatran etexilate, lepirudin, desirudin and bivalirudin, which bind to thrombin and block its enzymatic activity, are widely and effectively used in the treatment of thromboembolic diseases. DTIs appear to overcome the disadvantages of indirect thrombin inhibitors such as unfractionated heparins (UFH). Although these DTIs show specific advantages over indirect inhibitors, they still present limitations, such as a narrow therapeutic window, and bleeding and anaphylaxis as side-effects. Novel anticoagulant drugs need thus to be developed to overcome these limitations. In the search for additional candidate agents with improved efficacy, safety and high bioavailability in oral administration, a high number of compounds has been identified, such as those derived from the tripeptide template D-Phe-Pro-Arg, aptamers and peptides isolated from blood-sucking animals. These candidates may prove the new agents of choice for the treatment of cardiovascular diseases.

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P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold

Cited by 21 publications

References 15 publications

Peptidomimetics and their Applications in Antifungal Drug Design

Peptidomimetics and their Applications in Antifungal Drug Design

Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents

Direct thrombin inhibitors: Patents 2002–2012 (Review)

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