Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists

Ojo, Babatunde; Dunbar, Philip G.; Durant, G. J.; Nagy, Péter; Huzl, James J.; Periyasamy, Sumudra; Ngur, Dan O.; El-Assadi, Afif A.; Hoss, Wayne; Messer, William S.

doi:10.1016/0968-0896(96)00152-6

Cited by 21 publications

(11 citation statements)

References 29 publications

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“…Over the past decade, several selective muscarinic agonists were developed incorporating a 1,4,5, 6-tetrahydropyrimidine moiety (Dunbar et al, 1993;Dunbar et al, 1994;Ojo et al, 1996;. The novel amidine derivatives exhibit excellent agonist activity at M 1 receptors expressed in cell lines and in brain, and very low activity at M 3 receptors Messer et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The utility of muscarinic agonists in the treatment of alzheimer’s disease

Messer

2002

J Mol Neurosci

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Alzheimer's disease is a progressive neurological disorder characterized by amyloid plaques and neurofibrillary tangles along with memory and cognitive deficits associated with a loss of basal forebrain cholinergic neurons. Efforts to treat Alzheimer's disease have focused on compounds that elevate cholinergic activity such as cholinesterase inhibitors and direct acting muscarinic and nicotinic agonists. Low efficacy and poor selectivity of available compounds have limited the clinical utility of muscarinic agonists. Recent studies suggesting a role for muscarinic agonists in regulating the production of A beta raise the possibility that selective M1 agonists could be useful in treating not only the symptoms, but also the underlying cause(s) of Alzheimer's disease. Thus, renewed efforts have focused on the development of compounds with improved selectivity for M1 receptors and lower toxicity. 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) is a potent M1 agonist with a low side effect profile that enhances memory function in animal models of Alzheimer's disease. The available preclinical data suggest that CDD-0102 may be useful in the treatment of Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

The utility of muscarinic agonists in the treatment of alzheimer’s disease

Messer

2002

J Mol Neurosci

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“…[14] Additionally, sterically congested aryl carboxylic acids are often excellent substrates in palladium-catalyzed transformations as ortho-substituents are known to facilitate the decarboxylation process. [15] Compounds with the amidine motif are of considerable interest in drug discovery and have been indicated as potential agents for the treatment of Alzheimers disease, [16] malaria, [17] and as inhibitors of acid-sensing ion channels, [18] platelet aggregation [19] and serine proteases. [20] Amidines are also useful precursors for the synthesis of a wide variety of heterocyclic ring systems such as quinazolines, [21,22] quinazolinones, [23] pyrimidines, [24,25] triazoles, [26] and benzimidazoles.…”

Section: Introductionmentioning

confidence: 99%

Decarboxylative Palladium(II)‐Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation

Rydfjord

Svensson

Trejos

et al. 2013

Chemistry A European J

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A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)2], 6-methyl-2,2′-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11 mmol h−1 by using a glass reactor with an inner diameter of 3 mm at a flow rate of 1 mL min−1.

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“…Amidines 1 represent an important pharmacophore in drug discovery and can be found in DNA and RNA binding diamidine diminazene, 2 ASIC inhibitors, 3 muscarinic agonists for the treatment of Alzheimer’s disease, 4 platelet aggregation inhibitors, 5 and, recently, serine protease inhibitors, 6 to give a few examples. Amidines are also useful precursors in the formation of various heterocyclic ring systems, e.g.…”

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confidence: 99%