Design and synthesis of human serine racemase inhibitors, a challenge to modulate NMDAR dysregulation and neurodegeneration induced.

Abstract

Mammalian Serine Racemase (SR) is a pyridoxal-5′-phosphate (PLP) dependent enzyme, responsible for the biosynthesis of the neurotransmitter D-Serine, which activates N-methyl-d-aspartate receptors (NMDAR) in the CNS. Inhibition of SR could be a means to control D-Serine levels, which on turn may limit the NMDAR- mediated neurotoxicity in neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and protect against cerebral ischemia. The aim of this work is to identify new compounds that can interact with SR with satisfactory potency and selectivity, either with a competitive or with a non-competitive mechanism of action. In particular, a number of cyclopropane-1,2-dicarboxylic acid derivatives were synthetized, leading to the identification of cis-(±)-cyclopropane-1,2-dicarboxylic acid, that interacts with the enzyme in a non-covalent manner and shows an affinity of ̴ 240 µM. However, as described herein, the modification of the hit compound was found to be particularly problematic. The search for covalent inhibitors, led to the synthesis of a second class of compounds that interact with the PLP moiety of the enzyme, and inhibit the enzyme in a time–dependent manner. This finding opens the possibility of exploring a new class of SR covalent inhibitors.