Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1263-1277 |
Number of pages | 15 |
Journal | Drug Design, Development and Therapy |
Volume | 14 |
DOIs | |
State | Published - 2020 |
Keywords
- 8-hydroxyquinoline
- CLBQ14
- Clioquinol
- Drug development
- Methionine aminopeptidase
- Pharmacokinetics
- Physicochemical
- Tissue distribution
- Heart
- Humans
- Macaca fascicularis
- Methionyl Aminopeptidases/antagonists & inhibitors
- Male
- Kidney
- Tissue Distribution
- Thermodynamics
- Molecular Structure
- Communicable Diseases/drug therapy
- Rats
- Chemistry, Physical
- Rats, Sprague-Dawley
- Enzyme Inhibitors/blood
- Animals
- Mice
- Oxyquinoline/analogs & derivatives
ASJC Scopus subject areas
- Drug Discovery
- Pharmacology
- Pharmaceutical Science