Preclinical and early clinical studies with BW 1370U87, a reversible competitive monoamine oxidase-A inhibitor.

BW 1370U87 is unique among potent inhibitors of monoamine oxidase-A (MAO-A) in that it contains no nitrogen. Like other MAO-A inhibitors, BW 1370U87 elevates neurotransmitter amines in the brain over the same dose range at which it exhibits positive activities in animal models of depressive illness. However, BW 1370U87 differs from most other MAO inhibitors in that its mechanism of action follows simple competitive kinetics, so that an unusually high concentration of tyramine in peripheral tissues may displace the inhibitor from MAO-A sites in the intestine and liver. In addition, BW 1370U87 concentrations in brains of rats appear much higher than in plasma, whereas extensive metabolism of the parent compound in the liver produces weaker MAO-A inhibitors with the same type of competitive mechanism. Early phase-I safety trials at acute doses up to 2,000 mg of BW 1370U87 showed no adverse reactions, whereas MHPG in urine was decreased, indicating that in vivo inhibition of MAO-A was achieved in humans. Thus BW 1370U87 represents a new agent with potential therapeutic application in depression and other CNS illnesses.