Reversible Inhibitors of Monoamine Oxidase-A (RIMAs): Robust, Reversible Inhibition of Human Brain MAO-A by CX157

Abstract

Reversible inhibitors of monoamine oxidase-A (RIMA) inhibit the breakdown of three major neurotransmitters, serotonin, norepinephrine and dopamine, offering a multi-neurotransmitter strategy for the treatment of depression. CX157 (3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide) is a RIMA, which is currently in development for the treatment of major depressive disorder. We examined the degree and reversibility of the inhibition of brain monoamine oxidase-A (MAO-A) and plasma CX157 levels at different times after oral dosing to establish a dosing paradigm for future clinical efficacy studies, and to determine whether plasma CX157 levels reflect the degree of brain MAO-A inhibition. Brain MAO-A levels were measured with positron emission tomography (PET) imaging and [ 11 C]clorgyline in 15 normal men after oral dosing of CX157 (20-80 mg). PET imaging was conducted after single and repeated doses of CX157 over a 24-h time course. We found that 60 and 80 mg doses of CX157 produced a robust dose-related inhibition (47-72%) of [ 11 C]clorgyline binding to brain MAO-A at 2 h after administration and that brain MAO-A recovered completely by 24 h post drug. Plasma CX157 concentration was highly correlated with the inhibition of brain MAO-A (EC 50 : 19.3 ng/ml). Thus, CX157 is the first agent in the RIMA class with documented reversible inhibition of human brain MAO-A, supporting its classification as a RIMA, and the first RIMA with observed plasma levels that can serve as a biomarker for the degree of brain MAO-A inhibition. These data were used to establish the dosing regimen for a current clinical efficacy trial with CX157.

Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

“…The only MAO-A inhibitor currently in development is CB2202 (TriRima™), aka CX157 or KP157 ( Figure 3). The drug candidate is a highly selective MAO-A inhibitor (IC 50 = 3.3 nM in human brain) with no apparent affinity for the MAO-B subtype (Fowler et al, 2010). Thereby CB2202 is more than 100-times more potent than moclobemide inhibiting MAO-A.…”

Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men

“…28 Here we hypothesized that that epigenetic mechanisms and individual variations in the sequence of the core promoter would modulate the epigenetic landscape of the MAOA locus, thereby influencing gene expression and individual brain MAO A activity level. We tested this hypothesis by measuring brain MAO A activity using PET with [ 11 C]clorgyline, a radiotracer with specificity for MAO A, 29,30 in 34 healthy non-smoking males (tobacco smoke inhibits MAO A 31 ) and analyzing the MAOA methylation in WBC by bisulphite conversion of genomic DNA and subsequent sequencing of cloned DNA products. More than one race 1 1…”

“…Healthy male subjects (n = 34) were enrolled after informed consent was obtained and confidentiality of information was assured. Subjects were comprised of two different study populations for studies of MAO inhibitor drugs 30 in which each volunteer had a baseline PET scan and provided a blood sample for DNA analysis. The baseline PET scan and DNA analysis for each subject was used for the present study.…”

Markov model of smoking cessation

“…The latter, analyzed here, are, therefore, not fully representative of smokers at large (28,29); they may be biased to more dependent smokers who have failed independent attempts to quit, leading them to participate in these clinical trials. Genetic predispositions play a role in determining who falls into and successfully struggles out of addiction (19). As we shall see, different subpopulations of smokers may be characterized by distinctive values of the parameters β and ρ.…”

“…The structure of the model does not differentiate smokers by age, sex, or severity of dependence, and it does not take into account the crucial variables of social context and genetic predispositions (16)(17)(18)(19). However, although the grammar of Eq.…”