Eugene D. Thorsett

Therapeutic approaches to Alzheimer’s disease

Several recent advances have provided new insights and possibilities in defining therapeutic targets for Alzheimers disease. Of particular importance is the identification of the beta-secretase enzyme and the demonstration that immunization of a transgenic mouse model of Alzheimers disease with Abeta(1-42) peptide can prevent or alleviate neuropathological features of the disease.

The Identification and Optimization of Orally Efficacious, Small Molecule VLA-4 Antagonists

The identification of orally active, small molecule antagonists of the alpha4beta1 integrin, VLA-4, could lead to therapeutic agents with utility in a number of clinical settings, including asthma, multiple sclerosis and IBD. Starting from CDR3 sequences conserved among neutralizing alpha4 antibodies, peptides were identified that antagonized VLA-4 mediated adhesion in vitro. Through a series of structural modifications, these peptides evolved into small molecules that exhibited high potency and selectivity for VLA-4 in cell adhesion assays. Finally, through the optimization of physical and pharmacokinetic properties, compounds were identified that exhibited oral activity in animal models of asthma and multiple sclerosis.

Chapter 21. Alzheimer's Disease: Current Therapeutic Approaches

Publisher Summary This chapter discusses the status of the active Alzheimers disease (AD) therapeutic approaches as well as some areas that are only beginning to see medicinal chemistry activity. Though the exact pathogenic mechanisms of AD remain elusive, it is known that many neurotransmitter systems are dysfunctional, neuronal calcium homeostasis is upset, processes are in motion that produce senile plaque and neurofibrillary tangles, and there is an inflammatory response associated with the disease. The lack of any proven biochemical diagnostic method for AD makes selection of the therapeutic targets difficult. The cholinergic hypothesis of AD is based on the reported reduction of cholinergic markers, such as acetylcholinesterase (AChE) and choline acetyltransferase (ChAT). According to this hypothesis medial forebrain, cholinergic neurons undergo progressive retrograde degeneration accounting for some of the cognitive impairments in patients with AD. Clinical studies on the AChE inhibitor tacrine (THA) in a small group of patients, with moderate to severe AD that showed improvements in cognitive function, resulted in intensified efforts to develop novel acetylcholine esterase inhibitors. Though subsequent clinical studies have produced mixed results, THA has been recommended by the FDA advisory panel for the approval for AD treatment. Cholinerrgic agonists, acting directly on muscarinic receptors, may improve the cholinergic dysfunction seen in AD in which the basal forebrain muscarinic neurons that predominantly express the presynaptic M2 receptors have been found to atrophy. The formation and the biological properties of amyloid plaque is an area of major interest (80) though considerable controversy surrounds the role of amyloid plaque in AD associated neuro-degeneration. If amyloid derived senile plaque is a primary cause of neuronal degeneration, then the inhibition of amyloid formation could provide agents with the potential to slow down or even stop the progression of AD. Senile plaque consists largely of a peptide fragment (An) derived from Alzheimer amyloid precursor protein (APP). Amyloid may be indirectly neurotoxic via the induction of an inflammatory response that could result in toxicity to neurons surrounding the inflamed plaque.

A series of C-Terminal amino alcohol dipeptide Aβ inhibitors

Potent, small molecule Aβ inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.

Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model

A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.