title: MDL 72,974A: a selective MAO-B inhibitor with potential for treatment of Parkinson's disease.
abstract: MDL 72,974A [(E)-2-(4-fluorophenethyl)-3-fluoroallylamine, hydrochloride] was designed to be a selective, mechanism-based irreversible inhibitor of monoamine oxidase type B (MAO-B). The compound is a potent, selective MAO-B inhibitor in vitro and in vivo. In vitro studies revealed an IC50 value (MAO-B) of 3.6 nM with 189-fold selectivity compared to MAO-A. In rats, profound inhibition of MAO-B was achieved after a single oral dose with an ED50 of 0.18 mg/kg; a dose 44 times this amount was required to inhibit MAO-A by 50%. Selectivity was maintained following chronic dosing. MDL 72,974A had minimal sympathomimetic effects and did not potentiate the cardiovascular effects of tyramine, even at 50 times the MAO-B inhibiting dose. This inhibitor was equally effective and well-tolerated in man. In human volunteers, potent inhibition of platelet MAO-B activity was observed at submilligram doses (ED50 = 90 micrograms) following a single oral dose. Upon multiple oral doses of 100 micrograms, as much as 80% of MAO-B could be inhibited. In phase II studies, MDL 72,974A is proving to be a useful adjunct to conventional therapy. Patients (250) with Parkinson's disease, treated once daily with either 1 or 4 mg, together with L-Dopa and a decarboxylase inhibitor (MadoparR or SinemetR), saw significant improvements in symptoms compared with those on standard therapy without the inhibitor.
authors.affiliation: Marion Merrell Dow Research Institute, Cincinnati, Ohio.
authors.forename: M G
authors.initials: MG
authors.lastname: Palfreyman
authors.forename: I A
authors.initials: IA
authors.lastname: McDonald
authors.forename: M
authors.initials: M
authors.lastname: Zreika
authors.forename: G
authors.initials: G
authors.lastname: Cremer
authors.forename: K D
authors.initials: KD
authors.lastname: Haegele
authors.forename: P
authors.initials: P
authors.lastname: Bey
mesh_terms: D000498:Allyl Compounds; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001792:Blood Platelets / Q000201:enzymology; D001921:Brain / Q000201:enzymology; D002082:Butylamines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*
chemical_list: D000498:Allyl Compounds; D000978:Antiparkinson Agents; D002082:Butylamines; D008996:Monoamine Oxidase Inhibitors; C058000:mofegiline; D008995:Monoamine Oxidase