Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease

Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ( 15 nM) is associated to a 30.7 ( 8.6% inhibition of the proaggregating action of AChE on the A and a moderate inhibition of A self-aggregation (34.9 ( 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.
J.M.C. thanks Dr. Ma. Luz de la Puente (Analytical Technologies Department, Lilly SA), and Dr. Ma. Angeles Martínez-Grau (Lilly SA) for the resolution of compound 11. J.M.C. and also R.L. thank MEC for a fellowship (AP20020576) and B.L. thanks CSIC for a I3P Training Contract. The present work has been supported by Fundación Teófilo Hernando, MEC grants BFI2003-02722; SAF2006- 08764-C02-01, SAF-2006-08540, SAF2006-1249, and CTQ2005- 09365, CAM (S/SAL-0275-2006), ISCIII [Red RENEVAS (RD06/0026/1002)], CSIC-GRICES project (2007PT-13), and Fundación La Caixa (Barcelona, Spain).