89226-75-5

Manidipine (89226-75-5) is a clinically useful antihypertensive.1,2 It is an inhibitor of L- and T-type calcium channels with high selectivity for vasculature.? Manidipine has recently been found to be an inhibitor (IC50 = 4.8 μM) of the SARS-CoV-2 main protease, 3CLpro.3 It also acts as an early entry inhibitor of human cytomegalovirus (EC50 = 3.57 μM) via inhibition of the Immediate-Early 2 (IE2) protein.4

aldosterone antagonist

Manidipine Dihydrochloride is a metabolite of Manidipine (M16400), a dihydropyridine calcium channel blocker that exhibits antihypertensive properties.

ChEBI: Manidipine dihydrochloride is a diarylmethane.

Synthesis of 3-(2-(4-phenylpiperazin-1-yl)ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate from 3-(2-(4-phenylpiperazin-1-yl)ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5- Dicarboxylate dihydrochloride was prepared in the following general procedure: manidipine base (2.25 kg) was dissolved in a solvent mixture of dichloromethane (6.75 L) and methanol (4.5 L) and cooled to 0-10°C. Concentrated hydrochloric acid (1.07 L) was slowly added dropwise under stirring, and after completion of the dropwise addition, the reaction was continued with stirring for 1 hour by keeping the temperature at 0-10 °C. Subsequently, methyl tert-butyl ether (13.5 L) was added to the reaction system and stirring was continued for 1 h. A large amount of solid was observed to precipitate. Filtration was carried out and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was mixed with dichloromethane (22 L), refluxed and pulped for 1 hour, then cooled to room temperature and filtered again. The filter cake was washed with a small amount of methyl tert-butyl ether and finally dried at 40-50 °C in a blast to give a yellow solid product (2.05 kg). The yield of this step was 81.8% and the purity of the product was 99.8869% (see Figure 2 for HPLC analysis).

T-type calcium channel

Kakihana et al. (1988), Antihypertensive effect of CV-4093·2HCl, a new calcium antagonist, in three rat models of hypertension; Jpn. J. Pharmacol., 48 223 McKeage (2004), Manidipine: a review of its use in the management of hypertension; Drugs, 64 1923 Ghahremanpour et al. (2020), Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2; ACS Med. Chem. Lett., 11 2526 Mercorelli et al. (2018), Repurposing the clinically approved calcium antagonist manidipine dihydrochloride as a new early entry inhibitor of human cytomegalovirus targeting the Immediate-Early 2 (IE2) protein; Antiviral Res., 150 130