<p>Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases</p>

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.

The Potential Role of the Methionine Aminopeptidase Gene PxMetAP1 in a Cosmopolitan Pest for Bacillus thuringiensis Toxin Tolerance

“…The 4th instar is in the prophase of pupation, which is an important stage of growth and development, with enhanced physiological and biochemical activities (e.g., food intake [ 70 ]). Higher expression of Methionine aminopeptidase, known to play an important role in maintaining normal cell function [ 39 ], in the 4th instar, therefore, is potentially linked with the growth and development of P. xylostella . The highest relative expression of the PxMetAP1 gene in the egg and adult stages may be related to its mediating processes, such as cell proliferation and skeletal tissue development [ 40 ].…”

“…They catalyze the cleavage of the N-terminal initiator methionine (iMet) in new peptide chains and arylamides (called N-terminal methionine excision (NME)), which is essential for protein and peptide synthesis [ 36 ]. NME is versatile and essential for the post-translational processing and homeostasis of newly synthesized proteins and peptides [ 37 , 38 ], as well as in maintaining the normal physiological functions of cells [ 39 ]. It has been found that there are differences in the expression of proteins involved in lipid metabolism, cytoskeleton growth, cell proliferation, and protein synthesis when the activity of MetAPs is disturbed [ 40 ].…”

Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure–Activity Relationships, and Perspectives

“…This compound presented an oral bioavailability of 39%, while also having a high distribution in the body. 132 Researchers have also focused on the search of 8HQ derivative inhibitors of MetAP from Burkholderia pseudomallei (BpMetAP). 20 B. pseudomallei is an opportunistic bacteria causing melioidosis, a critical infection, which has few treatment options due to the pathogen's intrinsic resistance to several antimicrobial classes.…”

“…In a recent study, the pharmacokinetic properties of 38c were evaluated in vivo (in rats), which is useful to gain insights on the preclinical profile of this derivative. This compound presented an oral bioavailability of 39%, while also having a high distribution in the body …”

Structural and Photodynamic Studies on Nitrosylruthenium-Complexed Serum Albumin as a Delivery System for Controlled Nitric Oxide Release

“…Scheme shows the structures of the H5cqn ligand and its Ru-NO complex. The derivatives of 8-hydroxyquinoline are privileged scaffolds for drug candidates that have been widely explored for their biological effects such as neuroprotection, anticancer, anti-HIV, and antifungal effects. − It is possible to use halogen-substituted 8-quinolinols to increase the activity of drugs such as the well-known clioquinol. − In addition to the structural information, the results of various spectroscopic analyses provide insights into the potential application of the HSA complex adduct as an appropriate delivery system for biomedicine.…”