Pharmacokinetic evaluation of C-3 modified 1, 8-naphthyridine-3-carboxamide derivatives with potent anticancer activity: lead finding. (October 2014)

• Record Type: Journal Article
• Authors: Awasthi, Anshumali; Lohani, Mohtashim; Singh, Manoj K.; Singh, Anu T.; Jaggi, Manu
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 29:Number 5(2014:Oct.)
• Page Start: 710
• Page End: 721
• Publication Date: 2014-10
• Subjects: Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2013.845817
• Languages: English
• ISSNs: 1475-6366

Abstract

<abstract> <title>Abstract</title> <p>To develop naphthyridine derivatives as anticancer candidates, pharmacokinetic (PK) evaluations of 10 novel derivatives of 1, 4-dihydro-4-oxo-1-proparagyl-1, 8-naphthyridine-3-carboxamide, with potent anticancer activity were done using <italic>in vitro</italic> ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic--pharmcodynamic (PK/PD) assays. Only derivatives <bold>5</bold>, <bold>6</bold>, <bold>9</bold> and <bold>10</bold> showed better metabolic stability, solubility, permeability, partition coefficient and cytochrome P450 (CYP) inhibition values. PK of derivatives <bold>5</bold>, <bold>6</bold>, <bold>9</bold> and <bold>10</bold> in rat showed comparable PK profile for derivative <bold>5</bold> (C₀ = 6.98 µg/mL) and <bold>6</bold> (C₀ = 6.61 µg/mL) with no detectable plasma levels for derivatives <bold>9</bold> and <bold>10</bold> at 5.0 mg/kg <italic>i.v.</italic> dose. PK/PD assay of derivatives <bold>5</bold> and <bold>6</bold> in tumor-bearing mice (TBM) showed comparable PK but tumor plasma index (TPI) of derivative <bold>6</bold> (4.02) was better than derivative <bold>5</bold> (2.50), suggesting better tumor uptake of derivative <bold>6</bold>. Derivative <bold>6</bold>, as lead compound, showed highest tumor growth inhibition (TGI) value of 33.6% in human ovary cancer xenograft model.</p> </abstract>