DOI: 10.1002/cmdc.201300263 The Bivalent Ligand Approach as a Tool for Improving the in vitro Anti-Alzheimer Multitarget Profile of Dimebon Michela Rosini,* [a] Elena Simoni, [a] Manuela Bartolini, [a] Elena Soriano, [b] JosØ Marco- Contelles, [b] Vincenza Andrisano, [c] Barbara Monti, [a] Manfred Windisch, [d] Birgit Hutter-Paier, [d] David W. McClymont, [e] Ian R. Mellor, [e] and Maria Laura Bolognesi* [a] Alzheimer’s disease (AD) is an extremely challenging and often frustrating area of drug discovery. Since the withdrawal of ta- crine (Cognex) in 2006, more than 200 AD drug candidates have failed in late-stage clinical trials. [1] The antihistamine drug dimebon (1, Figure 1) belongs to this long list. In 2008, 1 at- tracted considerable interest within the AD community when it successfully completed a small six-month clinical trial in Russia, in which it showed impressive cognition-enhancing ef- fects in patients suffering from mild to moderate AD. [2, 3] How- ever, these positive outcomes were unconfirmed in a replica- tion trial in the United States. [4] We were particularly interested in 1 because, from initial re- ports on its in vitro activity profile, it seemed to fulfill the promise of an effective multitarget drug for treating AD. [5] In recent years, multitarget drug development has emerged as an effective approach in the search for disease-modifying drugs against AD. [6] This approach involves the development of single chemical entities that can simultaneously modulate multiple targets critically involved in the neurotoxic pathway. [7] It therefore runs parallel to drug combination in the search for appropriate therapeutic interventions against the complex pathogenesis of AD. [8, 9] Indeed, early research suggested that the clinical benefits of dimebon were related to its ability to simultaneously inhibit two crucial AD molecular targets: acetylcholinesterase (AChE) and N-methyl-d-aspartate receptor (NMDAR). [10] The effective- ness of simultaneous inhibition of both targets was further supported by higher short- and long-term efficacies observed in clinical trials involving co-administration of the NMDAR an- tagonist memantine and an AChE inhibitor (AChEI). Combining memantine and AChEIs is the current standard of care for AD patients. [11] Furthermore, pre-clinically, the combination was demonstrated to act synergistically, which may explain the ob- served clinical effects. [12] In this respect, we have already suc- cessfully combined the symptomatic relief of AChE inhibition and the neuroprotective action of NMDAR antagonism in a single multitarget molecule. [13, 14] In the case of 1, however, its low in vitro activity against these two key targets (IC 50 = 42 mm and 10–70 mm against AChE and NMDAR, respectively) might be one of the causes of its clinical failure. Indeed, Giorgetti et al. demonstrated that the brain concentration reached after acute oral administration of 1 to rats is much lower than that required to significantly affect AChE or NMDA pathways (nanomolar vs. micromolar). [15] Although exposure levels of dimebon in plasma and cerebro- spinal fluids in humans have not been published, it has been implied that the same situation might be replicated in the AD patients that were enrolled in the trial. [16] This raised much un- certainty on the real mechanism by which dimebon may bene- Figure 1. Design strategy for generating compounds 2–6. [a] Dr. M. Rosini, Dr. E. Simoni, Dr. M. Bartolini, Dr. B. Monti, Prof. M. L. Bolognesi Department of Pharmacy and Biotechnology University of Bologna, Via Belmeloro 6, 40126 Bologna (Italy) E-mail : michela.rosini@unibo.it marialaura.bolognesi@unibo.it [b] Dr. E. Soriano, Prof. J. Marco-Contelles Instituto de Quimica Organica General (CSIC) Juan de la Cierva, 3, 28006 Madrid (Spain) [c] Prof. V. Andrisano Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Rimini Campus, Italy [d] Dr. M. Windisch, Dr. B. Hutter-Paier JSW Lifesciences GmbH, Parkring 12, 8074 Grambach (Austria) [e] Dr. D. W. McClymont, Dr. I. R. Mellor School of Biology, University of Nottingham University Park, Nottingham NG7 2RD (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201300263.  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemMedChem 2013, 8, 1276 – 1281 1276 CHEMMEDCHEM COMMUNICATIONS