Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease.

Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Nov 21; 3(11): 928-40
Soper JH, Sugiyama S, Herbst-Robinson K, James MJ, Wang X, Trojanowski JQ, Smith AB, Lee VM, Ballatore C, Brunden KR

A hallmark pathological feature of the Alzheimer’s disease (AD) brain is the presence of senile plaques, which comprise amyloid ? (A?) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2?III (iPF2?III). IPF2?III can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased A? production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2?III-induced increases of A? secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD.
HubMed – drug

 

Targeting Selective Activation of M(1) for the Treatment of Alzheimer’s Disease: Further Chemical Optimization and Pharmacological Characterization of the M(1) Positive Allosteric Modulator ML169.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Nov 21; 3(11): 884-95
Tarr JC, Turlington ML, Reid PR, Utley TJ, Sheffler DJ, Cho HP, Klar R, Pancani T, Klein MT, Bridges TM, Morrison RD, Blobaum AL, Xiang Z, Daniels JS, Niswender CM, Conn PJ, Wood MR, Lindsley CW

The M(1) muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimer’s disease (AD) and schizophrenia. Moreover, M(1) interacts with BACE1 and regulates its proteosomal degradation, suggesting selective M(1) activation could afford both palliative cognitive benefit as well as disease modification in AD. A key challenge in targeting the muscarinic acetylcholine receptors is achieving mAChR subtype selectivity. Our lab has previously reported the M(1) selective positive allosteric modulator ML169. Herein we describe our efforts to further optimize this lead compound by preparing analogue libraries and probing novel scaffolds. We were able to identify several analogues that possessed submicromolar potency, with our best example displaying an EC(50) of 310 nM. The new compounds maintained complete selectivity for the M(1) receptor over the other subtypes (M(2)-M(5)), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogues were able to potentiate CCh-mediated nonamyloidogenic APPs? release, further strengthening the concept that M(1) PAMs may afford a disease-modifying role in the treatment of AD.
HubMed – drug

 

Stabilizers of neuronal and mitochondrial calcium cycling as a strategy for developing a medicine for Alzheimer’s disease.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Nov 21; 3(11): 873-83
Fernández-Morales JC, Arranz-Tagarro JA, Calvo-Gallardo E, Maroto M, Padín JF, García AG

For the last two decades, most efforts on new drug development to treat Alzheimer’s disease have been focused to inhibit the synthesis of amyloid beta (A?), to prevent A? deposition, or to clear up A? plaques from the brain of Alzheimer’s disease (AD) patients. Other pathogenic mechanisms such as the hyperphosphorylation of the microtubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instance, with inhibitors of the enzyme glycogen synthase-3 kinase beta (GSK3?). However, in spite of their proven efficacy in animal models of AD, all these compounds have so far failed in clinical trials done in AD patients. It seems therefore desirable to explore new concepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca(2+) channels (VDCCs) and on the mitochondrial Na(+)/Ca(2+) exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of AD patients. In recent years, evidence has accumulated indicating that enhanced neuronal Ca(2+) cycling (NCC) and futile mitochondrial Ca(2+) cycling (MCC) are central stage in activating calpain and calcineurin, as well as the intrinsic mitochondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional contributing factor to neuronal death is the excess free radical production linked to distortion of Ca(2+) homeostasis. We propose that an hybrid compound containing a dihydropyridine moiety (to block L channels and mitigate Ca(2+) entry) and a benzothiazepine moiety (to block the MNCX and slow down the rate of Ca(2+) efflux from the mitochondrial matrix into the cytosol), as well as a polyphenol moiety (to sequester excess free radicals) could break down the pathological enhanced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, such a trifunctional compound could eventually become a neuroprotective medicine capable of delaying disease progression in AD patients.
HubMed – drug

 

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid ?-Peptide Aggregation for the Treatment of Alzheimer’s Disease.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Nov 21; 3(11): 845-56
Lemkul JA, Bevan DR

The pathogenic aggregation of the amyloid ?-peptide (A?) is considered a hallmark of the progression of Alzheimer’s disease, the leading cause of senile dementia in the elderly and one of the principal causes of death in the United States. In the absence of effective therapeutics, the incidence and economic burden associated with the disease are expected to rise dramatically in the coming decades. Targeting A? aggregation is an attractive therapeutic approach, though structural insights into the nature of A? aggregates from traditional experiments are elusive, making drug design difficult. Theoretical methods have been used for several years to augment experimental work and drive progress forward in Alzheimer’s drug design. In this Review, we will describe how two common techniques, molecular docking and molecular dynamics simulations, are being applied in developing small molecules as effective therapeutics against monomeric, oligomeric, and fibrillated forms of A?. Recent successes and important limitations will be discussed, and we conclude by providing a perspective on the future of this field by citing recent examples of sophisticated approaches used to better characterize interactions of small molecules with A? and other amyloidogenic proteins.
HubMed – drug

 

 

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