Aminopyridazines as Acetylcholinesterase Inhibitors

Abstract

Following the discovery of the weak, competitive and reversible acetylcholinesterase (AChE)-inhibiting activity of minaprine (3c) (IC50 = 85 microM on homogenized rat striatum AChE), a series of 3-amino-6-phenylpyridazines was synthesized and tested for inhibition of AChE. A classical structure-activity relationship exploration suggested that, in comparison to minaprine, the critical elements for high AChE inhibition are as follows: (i) presence of a central pyridazine ring, (ii) necessity of a lipophilic cationic head, (iii) change from a 2- to a 4-5-carbon units distance between the pyridazine ring and the cationic head. Among all the derivatives investigated, 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-6-phenylpyridazine (3y), which shows an IC50 of 0.12 microM on purified AChE (electric eel), was found to be one of the most potent anti-AChE inhibitors, representing a 5000-fold increase in potency compared to minaprine.1

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

“…The syntheses of pyridonepezils 14−17 (Chart 1) have been carried out by N-alkylation of readily available ethyl 6-chloro-5-cyano-2-methyl-4-phenylnicotinate (22) 41 with commercial 4-amino-1-benzylpiperidine (23), (1-benzylpiperidin-4-yl)-methanamine (24), 42 2-(1-benzylpiperidin-4-yl)ethanamine (25), 42 and 3-(1-benzylpiperidin-4-yl)propan-1-amine (26) 43 in high yield (Scheme 1).…”

“…The most potent and selective inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) 51 The inhibitory activities of the hybrids were compared to those determined for the parent compound, donepezil. 42 Unfortunately, compound 14 was not soluble; thus, biological assessment was not possible. Pyridonepezils 15−18 were found to be selective and moderately potent regarding the inhibition of hAChE, with IC 50 values in the submicromolar range (from 0.25 to 4.57 μM, Table 2).…”

“…32 Aβ interaction with the plasma membrane results in elevated [Ca 2+ ] i and increased vulnerability of neurons to excitotoxicity. Oligomeric forms of Aβ 42 cause Ca 2+ -mediated toxicity in cultured cells. Degenerative changes occur in neurites associated with Aβ deposits in APP mutant mice, suggesting the involvement of Ca 2+ -mediated Aβ neurotoxicity in vivo.…”

Analogues as a Means of Discovering New Drugs

“…It transpired that minaprine had only a very weak affinity for acetylcholinesterase (600 lM on electric eel enzyme), but relatively simple modifications (creation of a lipophilic cationic head, increase of the side chain length, and bridging the phenyl and the pyridazinyl rings) led to nanomolar affinities ( Fig. 1.18) [39,40]. …”

Synthesis and in‐vitro Cytotoxic Evaluation of Novel Pyridazin‐4‐one Derivatives

“…Pyridazine derivatives, in particular pyridazinones, present various pharmacological properties [1][2][3][4][5]. Introduction of an aryl moiety on the pyridazinone skeleton has resulted in a large number of derivatives exhibiting a plethora of promising pharmacological activities.…”