Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. I. Studies in the rat

Abstract

1. The metabolic fate of a new anti-hypertensive, 1-pyrrolyl pyridazinamine, was studied in male Wistar rats after both p.o. and i.v. administration (1 mg/kg)

2. The compound undergoes rapid metabolism, disappearing from the central compartment with a half-life of about 0.5 h. Plasma concn. of the parent drug and its major metabolite I following i.v. and p.o. administration suggest a route-dependent first-pass metabolism.

3. Ten metabolites were isolated from the urine and identified by u.v., i.r., mass and ¹H-n.m.r. spectroscopy. The structure of some was confirmed by ¹³C-n.m.r. and chemical synthesis.

4. All biotransformations are restricted to the pyrrole ring which undergoes oxidative cleavage followed by a series of chemical rearrangements. A minor pathway leads to the formation of methyl sulphinyl and methyl sulphonyl pyrroles. It is suggested that, as with natural indoles, the pyrrole might be oxidized by a 2,3-dioxygenase.

5. The three major metabolites, I, II and IX, along with two minor ones, VI and VII, were inactive when tested i.v. for antihypertensive activity.