Lomerizine Hydrochloride

Migraine is one of the most disabling diseases with a significant socioeconomic impact. Approximately 8.4% of Japanese people experience migraines. In Japan, five types of triptans have been approved since the year 2000. Furthermore, the development of lomerizine and the approval of valproic acid and propranolol for migraine prophylaxis have greatly improved the treatment of patients with migraines. The 2006 Clinical Practice Guidelines for Chronic Headache were published by the Japanese Headache Society and prompted evidence-based migraine treatment. However, we did not obtain satisfactory results. Since 2021, the number of new treatment options in Japan will increase. Some patients with migraines do not benefit from the poor efficacy, side effects, or vasoconstrictive effects of triptan. Selective 5-hydroxytryptamine (HT) 1F receptor agonist (ditan), which does not stimulate the 5-HT 1B receptor, can compensate for the shortcomings of triptan. Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a vital role in migraine pathophysiology and is a target for migraine preventive therapies. Monoclonal antibodies targeting CGRP (galcanezumab and fremanezumab) and its receptor (erenumab) have shown consistent efficacy in migraine prophylaxis, with excellent safety profiles. Its effects on refractory cases have also been reported, and a paradigm shift in migraine treatment is emerging.

Chikungunya fever is an acute infectious disease caused by Chikungunya virus (CHIKV) and transmitted by Aedes mosquito. It is characterized by fever, rash and arthralgia with no effective drugs. Lomerizine (Lom) is a new generation calcium antagonist, which is mainly used in the treatment of migraine. Certain antiviral function of Lom was shown by some research. In our study, a series of new derivatives of Lom were designed and synthesized, and their in-vitro anti-CHIKV activity was tested. The results showed that Lom and its derivatives had potent anti-CHIKV activity and low cytotoxicity. Among them, compounds B1 and B7 showed most potent antiviral activity. Besides, structure-activity relationships, in-silico ADMET properties were also analyzed. Molecular docking study was performed to rationalize the SAR and analyze the possible binding modes between B1 and amino acid residues in the active site of nsP3 protein to enhance the understanding of their action as antiviral agents. These finding provides research basis for the design and synthesis of effective anti-CHIKV drugs with Lom as the lead compound.