Pre-clinical pharmacokinetics, tissue distribution and physicochemical studies of CLBQ14, a novel methionine aminopeptidase inhibitor for the treatment of infectious diseases
Drug Design, Development and Therapy, ISSN: 1177-8881, Vol: 14, Page: 1263-1277
2020
- 11Citations
- 27Captures
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Metrics Details
- Citations11
- Citation Indexes11
- 11
- Captures27
- Readers27
- 27
Article Description
Introduction: CLBQ14, a derivative of 8-hydroxyquinoline, exerts its chemotherapeutic effect by inhibiting methionine aminopeptidase (MetAP), the enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP is a novel target for infectious diseases. CLBQ14 is selective and highly potent against replicating and latent Mycobacterium tuberculosis making it an appealing lead for further development. Methods: The physicochemical properties (solubility, pH stability and lipophilicity), in vitro plasma stability and metabolism, pre-clinical pharmacokinetics, plasma protein binding and tissue distribution of CLBQ14 in adult male Sprague-Dawley rats were characterized. Results: At room temperature, CLBQ14 is practically insoluble in water (<0.07 mg/mL) but freely soluble in dimethyl acetamide (>80 mg/mL); it has a log P value of 3.03 ± 0.04. CLBQ14 exhibits an inverse Z-shaped pH decomposition profile; it is stable at acidic pH but is degraded at a faster rate at basic pH. It is highly bound to plasma proteins (>91%), does not partition to red blood cells (B/P ratio: 0.83 ± 0.03), and is stable in mouse, rat, monkey and human plasma. CLBQ14 exhibited a bi-exponential pharmacokinetics after intravenous administration in rats, bioavailability of 39.4 and 90.0%, respectively from oral and subcutaneous route. We observed a good correlation between predicted and observed rat clearance, 1.90 ± 0.17 L/kg/h and 1.67 ± 0.08 L/kg/h, respectively. Human hepatic clearance predicted from microsomal stability data and from the single species scaling were 0.80 L/hr/kg and 0.69 L/h/kg, respectively. CLBQ14 is extensively distributed in rats; following a 5 mg/kg intravenous administration, lowest and highest concentrations of 15.6 ± 4.20 ng/g of heart and 405.9 ± 77.11 ng/g of kidneys, respectively, were observed. In vitro CYP reaction phenotyping demonstrates that CLBQ14 is metabolized primarily by CYP 1A2. Conclusion: CLBQ14 possess appealing qualities of a drug candidate. The studies reported herein are imperative to the development of CLBQ14 as a new chemical entity for infectious diseases.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85083261909&origin=inward; http://dx.doi.org/10.2147/dddt.s238148; http://www.ncbi.nlm.nih.gov/pubmed/32280198; https://www.dovepress.com/pre-clinical-pharmacokinetics-tissue-distribution-and-physicochemical--peer-reviewed-article-DDDT; https://dx.doi.org/10.2147/dddt.s238148; https://www.dovepress.com/pre-clinical-pharmacokinetics-tissue-distribution-and-physicochemical--peer-reviewed-fulltext-article-DDDT
Informa UK Limited
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