Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug.

  title={Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug.},
  author={Alessandro Assandri and Giorgio Tarzia and Elvio Bellasio and Romeo Ciabatti and G. Tuan and Pietro Ferrari and Luigi F. Zerilli and Moreno Lanfranchi and G Pelizzi},
  journal={Xenobiotica; the fate of foreign compounds in biological systems},
  volume={17 5},
The metabolism of the anti-hypertensive drug, mopidralazine, N-(2',5'-dimethyl-1H-pyrrol-1-yl)-6-(4"-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2'(5')-13CH3]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine. The previously proposed mesonic structure of the major metabolite I, i.e., 5'-hydroxy-3',6'-dimethyl-1'-[6-(4"-morpholinyl)-3-pyridazinyl]pyrida zinium hydroxide inner salt, was… 
Development of new HPLC method for identification of metabolic degradation of N-pyrrolylhydrazide hydrazones with determined MAO- B activity in cellular cultures
A new rapid PR- HPLC method was developed for the determination of metabolites in isolated rat hapatocytes and identified as first step of metabolism the hydrolysis of the hydrazone group.
Scaffold-hopping as a strategy to address metabolic liabilities of aromatic compounds.
A review of recent examples where different scaffold-hopping approaches were used to reduce metabolic clearance or block the formation of reactive metabolites in lead optimization.
Structural Alerts for Toxicity
This chapter summarizes structural alerts where there is a significant weight of evidence that their incorporation into a drug candidate molecule is likely to result in a higher than average
Structural Alerts for Toxicity
  • Medicinal Chemistry for Practitioners
  • 2020


Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog.
The metabolic fate of a new anti-hypertensive, 1- pyrrolyl-pyridazinamine, was studied in male Beagle dogs given both p.o.r. and i.v. doses of the 14C-labelled drug and was shown to be inactive.
Antihypertensives. N-1H-Pyrrol-1-yl-3-pyridazinamines.
The hypothesis that the side effects of hydralazine, such as mutagenicity and lupus erythematosus like syndrome, might be due to the NHNH2 group prompted us to incorporate part of this moiety into a pyrrole ring, which showed no mutagenic activity in several tests and is now in clinical trials in patients.
Pharmacological studies of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899), a new long-acting antihypertensive vasodilator.
MDL-899 given orally to rats has no important depressant effects on the CNS at hypotensive or higher doses and induces no adrenergic system stimulation symptoms (midriasis, exophthalmus).
Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog.
The ratio between the plasma concentrations of 14C and of unchanged MDL-899 indicates rapid metabolic transformation and, especially in the rat, a marked first-pass effect, and the time course of the pharmacological response seems to be correlated to the kinetics of the active species in deep-compartment(s) rather than to the plasma concentration.
Metabolic activation of model pyrroles by cytochrome P-450.
Results indicate that cytochromes P-450 can activate pyrroles to more electrophilic species capable of binding irreversibly to biological macromolecules.
Metabolic fate of premazepam, a new anti-anxiety drug, in the rat and the dog.
Unchanged premazepam is cleared faster in rats than in dogs, with half-lives about 1.7 and 2.7 hr, respectively, and following oral dosage, two-thirds of the dose is eliminated in urine.
Pyrrolooxygenases: isolation, properties, and products formed.
Studies on indoleamine 2,3-dioxygenase. I. Superoxide anion as substrate.
Metabolism of pirprofen in man, monkey, rat, and mouse.
Pirprofen was well absorbed by man, rhesus monkey, rat, and mouse after oral administration of a solution of 14C-labeled compound, and metabolites of pirprofen, accounting for 80% or more of the urinary radioactivity, were identified in the urine of the four species.
Synthesis of N‐(2, 5‐[2‐13C]dimethyl‐1H‐pyrrol‐1‐YL)‐6‐(4‐morpholinyl)‐3‐Pyridazinamine hydrochloride
N-(2, 5-[2-13C]dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride ([2-13C]methyl MDL-899), a new antihypertensive agent, was synthesized for metabolic studies, in five steps