Calcium channel blockers’ contribution to overcoming Current drug discovery challenges in Alzheimer’s disease

ABSTRACTIntroduction Alzheimer’s disease (AD) is a progressive, irreversible, and multifactorial brain disorder that gradually and insidiously destroys individual’s memory, thinking, and other cognitive abilities.Areas covered In this perspective, the authors examine the complex and multifactorial nature of Alzheimer’s disease and believe that the best approach to develop new drugs is the MTDL strategy, which obviously faces several challenges. These challenges include identifying the key combination of targets and their suitability for coordinated actions, as well as developing an acceptable pharmacokinetic and toxicological profile to deliver a drug candidate.Expert opinion Since calcium plays a crucial role in the pathology of AD, a polypharmacological approach with calcium channel blockers reinforced by activities targeting other factors involved in AD is a serious option in our opinion. This is exemplified by a phase III clinical trial using a drug combination approach with Losartan, Amlodipine (a calcium channel blocker), and Atorvastatin, as well as several MTDL-based calcium channel blockade approaches with a promising in vitro and in vivo profile.KEYWORDS: Alzheimer’s diseasecalcium channel blockadeMtdls14-dihydropyridinedihydropyrimidinone Article highlights Alzheimer’s disease is a progressive, irreversible, and multifactorial brain disorder that gradually destroys an individual’s memory, thinking, and other cognitive abilities.Calcium dysregulation is responsible for a wide range of pathological changes in the brain. It is commonly associated with several features, risk factors, and genetic mutations related to Alzheimer’s disease.The currently available drugs consist of four small molecules that target a single receptor, acting by either inhibiting acetylcholinesterase or blocking the N-methyl-D-aspartate receptor, and two monoclonal antibodies that can reduce Aβ plaques in the brain but have limited efficacy.The polypharmacological approach seems to be the best option to develop new drug for Alzheimer’s disease and particularly multi-target-directed ligands strategy versus drug combination.The development of multi-target-directed ligands with synergetic targets including calcium channel blockade is a serious option.1,4-DHP and DHPMs are the most studied scaffold for generating calcium channel blockers and which can be easily obtained through the Hantzsch and Biginelli reactions.Several multi-target-directed ligands based on 1,4-DHP and DHPMs, which target calcium channel blockade exhibit promising pharmacological profiles along with in vivo proof of concept, have been developed.Declaration of interestThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe authors are supported by the University of Franche-Comté and the Regional Council of Bourgogne-Franche-Comté (2022Y-13659 and the 13660 ACCURATE PROJECT).