Preclinical pharmacokinetics of the 3-carbamyl-4-methylpyrrole analog, MNP001, a novel antihypertensive agent.

摘要

Chemically synthesized 3-carbamyl-4-methylpyrroles were characterized as a group of antihypertensive agents with dual-targeting mechanism to simultaneously inhibit type 4 phosphodiesterase (PDE4) and L-type calcium channels. A 5-butyl analog of the pyrrole family, MNP001, was found to have high potency in reducing animal blood pressure and heart rate. The goal of this research is to evaluate the physicochemical properties, preclinical pharmacokinetics and drug metabolism of MNP001 and as a requisite for these studies, bio-analytical assay methodology for the quantification of MNP001 concentrations in biological samples were developed and validated.;First, sensitive, specific and accurate bio-analytical methods were developed and validated to determine the concentrations of MNP001 in rat plasma or other biological samples. Then, the physicochemical properties of MNP001, including solubility, pKa, Log P, plasma protein binding and plasma/blood partitioning, were determined to support the pharmacokinetic characterization. Next, the pharmacokinetic disposition of MNP001 was investigated in rats after a single intravenous or oral dose. The pharmacokinetic analysis was conducted to describe plasma drug concentrations over time and predict the essential parameters associated with drug absorption, distribution and elimination. Furthermore, metabolic stability and major metabolic pathway of MNP001 were characterized after incubation with rat and human microsomes/supersomes fortified with proposed incubational cofactors.;The bio-analytical methods for measuring the MNP001 in rat plasma and other biological samples were sensitive, specific and accurate. MNP001 was found to have a low solubility in simulated intestinal fluid but a high solubility in simulated gastric fluid. MNP001 was a highly lipophilic compound with a Log P value greater than 4. MNP001 was highly bound to the plasma protein and mostly distributed into the plasma compartment. MNP001 exhibited a broad distribution, slow systemic clearance and low oral bioavailability in rats. MNP001 had prolonged blood pressure lowering efficacy for 48 hours after intravenous dosing and 8 hours after oral dosing. MNP001 was primarily metabolized by a CYP450 catalyzed phase I dehydrogenation reaction. The in vitro rate of oxidative metabolism was much higher in rat microsomes than in human microsomes. The incomplete oral bioavailability of MNP001 suggested the possibility of high first-pass metabolism, low solubility and/or low gastro-intestinal permeability.;A future study will be carried out to improve the oral bioavailability of MNP001 or discover other new chemical entities with more favorable pharmacokinetics and pharmacodynamics for the treatment of hypertension. Additionally, stereoselective drug dispositions, species-specific differences, and drug interactions will be evaluated to achieve a more complete preclinical pharmacokinetic study.