Preclinical pharmacokinetics and metabolism of MNP001, a piperidine analog of 3-carbamyl compounds

摘要

MNP001 is a newly synthesized 3-carbamyl-4-methylpyrrole analog with dual pharmacophores simultaneously to inhibit phosphodiesterase type 4 (PDE4) and to antagonize L-type calcium channels. The physicochemical properties of MNP001, including solubility, pKa, Log P, plasma protein binding and plasma/blood partitioning, were determined to support the pharmacokinetic characterization. The preclinical pharmacokinetic parameters were determined in an in vivo rat model and the metabolic pathways of MNP001 were characterized by incubating the compound in vitro in rat or human microsomes/supersomes cocktails. MNP001 was found to have a low solubility in simulated intestinal fluid but a high solubility in simulated gastric fluid. MNP001 is a highly lipophilic compound with a Log P value greater than 4. MNP001 was highly bound to the plasma protein and had an uneven partition between red blood cells and plasma. MNP001 exhibited a rapid absorption, broad distribution, slow systemic clearance and a low but pharmacologically relevant oral bioavailability in rats. The low oral bioavailability was possibly caused by the low aqueous solubility of MNP001 in the gastrointestinal tract. However, 8?h after oral dosing, the mean plasma level of MNP001 was able to remain about 2-fold greater than the minimum effective concentration. The major metabolite of MNP001 was defined as a tetrahydropyridine product (MNP001-M4) of CYP3A4-mediated phase I oxidation. The possibility that the major metabolite MNP001-M4 may have a comparable antihypertensive efficacy to MNP001 needs to be studied. Copyright ? 2010 John Wiley & Sons, Ltd.