Chiral inversion of RS‐8359: A selective and reversible MAO‐A inhibitor via oxido‐reduction of keto‐alcohol

Abstract

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine is a selective and reversible MAO-A inhibitor. The (S)-enantiomer of RS-8359 has been demonstrated to be inverted to the (R)-enantiomer after oral administration to rats. In the current study, we investigated the chiral inversion mechanism and the properties of involved enzymes using rat liver subcellular fractions. The 7-hydroxy function of RS-8359 was oxidized at least by the two different enzymes. The cytosolic enzyme oxidized enantiospecifically the (S)-enantiomer with NADP as a cofactor. On the other hand, the microsomal enzyme catalyzed more preferentially the oxidation of the (S)-enantiomer than the (R)-enantiomer with NAD as a cofactor. With to product enantioselectivity of reduction of the 7-keto derivative, it was found that only the alcohol bearing (R)-configuration was formed by the cytosolic enzyme with NADPH and the microsomal enzyme with NADH at almost equal rate. The reduction rate was much larger than the oxidation rate of 7-hydroxy group. The results suggest that the chiral inversion might occur via an enantioselectivity of consecutive two opposing reactions, oxidation and reduction of keto-alcohol group. In this case, the direction of chiral inversion from the (S)-enantiomer to the (R)-enantiomer is governed by the enantiospecific reduction of intermediate 7-keto group to the alcohol with (R)-configuration. The enzyme responsible for the enantiospecific reduction of the 7-keto group was purified from rat liver cytosolic fractions and identified as 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) via database search of peptide mass data obtained by nano-LC/MS/MS.

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

“…24 (RS-8359) is a selective and reversible monoamine oxygenase inhibitor under examination for treatment of depression 74. Clinical studies75 demonstrate different efficacies for the two enantiomers of 24 and an in vivo epimerization through oxidation and reduction of the benzylic alcohol 76…”

Chirality of Biomolecules and Biotechnology Products

“…The chiral inversion mechanism and the properties of involved enzymes were investigated using rat liver subcellular fractions [50]. (±)-4-(4-Cyanoanilino)-5, 6-dihydro-7-hydroxy-7H -cyclopentad-pyrimidine is a selective and reversible MAO-A inhibitor.…”

Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity

“…However, they were withdrawn due to their toxic side effects . Subsequently, different families of heterocycles containing 2 or 4 nitrogen atoms were used as scaffolds for synthesizing reversible and selective MAO inhibitors . 2‐Pyrazolines, which form one of these families, can also be considered as a cyclic hydrazine derivative.…”

“…16 Subsequently, different families of heterocycles containing 2 or 4 nitrogen atoms were used as scaffolds for synthesizing reversible and selective MAO inhibitors. [17][18][19][20][21][22][23] 2-Pyrazolines, which form one of these families, can also be considered as a cyclic hydrazine derivative. On the basis of the clinical profiles of hydrazine and other heterocycles, researchers focused on structural modifications of the pyrazoline to enhance the pharmacological activity.…”