The synthesis of amide bonds is one of the most frequently performed reactions in pharmaceutical synthesis, but the requirement for stoichiometric quantities of coupling agents and activated substrates in established methods has prompted interest in biocatalytic alternatives. Amide Bond Synthetases (ABSs) actively catalyze both the ATP-dependent adenylation of carboxylic acid substrates and their subsequent amidation using an amine nucleophile, both within the active site of the enzyme, enabling the use of only a small excess of the amine partner. We have assessed the ability of an ABS from Streptoalloteichus hindustanus (ShABS) to couple a range of carboxylic acid substrates and amines to form amine products. ShABS displayed superior activity to a previously studied ABS, McbA, and a remarkable complementary substrate specificity that included the enantioselective formation of a library of amides from racemic acid and amine coupling partners. The X-ray crystallographic structure of ShABS has permitted mutational mapping of the carboxylic acid and amine binding sites, revealing key roles for L207 and F246 in determining the enantioselectivity of the enzyme with respect to chiral acid and amine substrates. ShABS was applied to the synthesis of pharmaceutical amides, including ilepcimide, lazabemide, trimethobenzamide, and cinepazide, the last with 99% conversion and 95% isolated yield. These findings provide a blueprint for enabling a contemporary pharmaceutical synthesis of one of the most significant classes of small molecule drugs using biocatalysis.

01 Jan 2023·Toxicology and Applied Pharmacology

Drug repurposing of ilepcimide that ameliorates experimental autoimmune encephalomyelitis via restricting inflammatory response and oxidative stress

Article

Author: Huang, Jin ; Tang, Lu ; Wang, Wanyan ; Xu, Zhaomin ; Lu, Weiqiang ; Liu, Zehui ; Liu, Xi ; Lu, Sisi ; Cui, Jiayan

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that remains incurable. Herein, we demonstrated that ilepcimide (Antiepilepsirine), an antiepileptic drug used for decades, protects mice from experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Our studies found that ilepcimide treatment effectively ameliorates demyelination, blood-brain barrier leakage and infiltration of CD4⁺ and CD8⁺ T cells in EAE mice. On the one hand, ilepcimide can inhibit dihydroorotate dehydrogenase (DHODH), an important therapeutic target for MS. Computer molecular docking, thermal shift and fluorescence quenching assay demonstrated the directly interaction between ilepcimide and DHODH. Accordingly, ilepcimide observably repressed T cell proliferation in mixed lymphocyte reaction (MLR) assay and concanavalin A (Con-A) model in a DHODH-dependent manner. On the other hand, ilepcimide exhibited neuroprotective effect possibly through activating NRF2 antioxidant pathway in mouse neural crest-derived Neuro2a cells. Collectively, our findings have revealed the therapeutic potential of ilepcimide in EAE mouse model via restricting inflammatory response and oxidative stress, offering a potential opportunity for repurposing existing drug ilepcimide for MS therapy.

01 Feb 2021·Epilepsy ResearchQ3 · MEDICINE

Ilepcimide inhibited sodium channel activity in mouse hippocampal neurons

Q3 · MEDICINE

Article

Author: Tang, Bin ; He, Na ; Qin, Bing ; Deng, Wei-Yi ; Long, Yue-Sheng ; Shi, Yi-Wu ; Zhao, Qi-Hua ; Liao, Wei-Ping ; Li, Bing-Mei ; Gao, Mei-Mei ; Zeng, Yang

Ilepcimide (ICM), a clinically effective antiepileptic drug, has been used in China for decades; however, its antiepileptic mechanism remains unclear. ICM is structurally similar to antiepileptic drug lamotrigine (LTG). LTG exerts its anticonvulsant effect by inhibiting voltage-gated Na⁺ channel (Na_V) activity. Thus it is speculated that ICM also exert its antiepileptic activity by inhibiting sodium channel activity. We studied the inhibition of Na_V activity by ICM in acutely isolated mouse hippocampal pyramidal neurons. We evaluated ICM-mediated tonic, concentration-dependent, and voltage-dependent inhibition of Na_V, and the effects of ICM and LTG on Na_V biophysical properties. Na⁺ currents in hippocampal pyramidal neurons were tonically inhibited by ICM in a concentration- and voltage-dependent manner. The half-maximal inhibitory concentration (IC₅₀) of ICM at a holding potential (V_h) of -90 mV was higher than that at a V_h of -70 mV. Compared with the control groups, in the presence of 10 μM ICM, the current densities of Na⁺ channels were reduced, the half-maximal availability of the inactivation curve (V_1/2) was shifted to more negative potentials, and the recovery from inactivation was delayed. These data can contribute to further investigation of the inhibitory effect of ICM on the sodium channel, suggesting that the main reason for the anticonvulsant effect of ICM is the small influx of sodium ions. ICM can prevent abnormal discharge of neurons, which may prevent epilepsy.

100 Deals associated with Ilepcimide

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KEGG	Wiki	ATC	Drug Bank
D04503	Ilepcimide	-	-

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