Background
Alzheimer’s disease (AD) is the leading cause of dementia and lacks disease‐modifying treatments. Tau‐based therapies are attractive and Tau reduction prevents amyloid‐induced dysfunction ...in preclinical AD models. Tau reduction also prevents amyloid‐independent dysfunction in diverse disease contexts, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau’s interaction with SH3 domain containing proteins likely underlie mechanisms of amyloid‐induced dysfunction, so we targeted their interaction as a therapeutic strategy.
Method
We previously designed a peptide Tau‐SH3 interaction inhibitor based on the region of Tau that binds FynSH3, and determined that it prevented amyloid‐induced dysfunction in primary neurons. We next completed a high‐throughput screen to identify compounds that inhibit Tau‐Fyn interaction. Here, we studied a top hit from that screen, generated and characterized a series of daughter compounds, and tested whether the compounds prevented amyloid‐induced dysfunction in primary neurons.
Result
The hit compound, SR31627, prevented amyloid‐β toxicity in primary neurons. The medicinal chemistry program resulted in lead compound SR42667, which had five‐fold improved potency and improved drug‐like properties. We found that SR42667 binds Tau, is cell‐permeable, and prevents amyloid‐induced dysfunction.
Conclusion
We demonstrate that Tau‐SH3 interactions can be targeted using small molecule inhibitors and that these inhibitors have efficacy for blocking amyloid‐induced dysfunction.
A novel series of potent 2-aryl pyrido2,3-
dpyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
A novel series of potent ...2-aryl pyrido2,3-
dpyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
Overwhelming evidence supports a central role for the amyloid beta-peptide (Abeta) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Abeta from its precursor protein APP ...are top targets for therapeutic intervention. Considerable effort has focused on targeting gamma-secretase, which generates the C-terminus of Abeta; however, gamma-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter gamma-secretase activity to reduce Abeta production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that gamma-secretase can be selectively inhibited in this way by naphthyl-substituted gamma-aminoketones and gamma-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing gamma-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological ...activities of these analogs are discussed.
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such ...neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure−activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Our interest in the area of m4 muscarinic antagonists has led us to study a series of benzoxazine isoquinolines. One of the most potent and selective compounds of this series is example
1 with an IC
...50 value of 90.7nM at m4 receptors, and 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82-fold (m5) more selective compared to the other receptors. The synthesis and receptor binding affinity of analogs of
1 are reported.
The study of a series of benzoxazine isoquinolines, which led to the identification of a potent and selective m4 muscarinic antagonist
1 is reported. For
1 at the m4 receptor, the IC
50 = 90.7 nM; however,
1 is 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82-fold (m5) more selective when compared to the other receptors.
HIV-1 Vpu targets the host cell proteins CD4 and BST-2/Tetherin for degradation, ultimately resulting in enhanced virus spread and host immune evasion. The discovery and characterization of small ...molecules that antagonize Vpu would further elucidate the contribution of Vpu to pathogenesis and lay the foundation for the study of a new class of novel HIV-1 therapeutics. To identify novel compounds that block Vpu activity, we have developed a cell-based ‘gain of function’ assay that produces a positive signal in response to Vpu inhibition. To develop this assay, we took advantage of the viral glycoprotein, GaLV Env. In the presence of Vpu, GaLV Env is not incorporated into viral particles, resulting in non-infectious virions. Vpu inhibition restores infectious particle production. Using this assay, a high throughput screen of >650,000 compounds was performed to identify inhibitors that block the biological activity of Vpu. From this screen, we identified several positive hits but focused on two compounds from one structural family, SRI-41897 and SRI-42371. We developed independent counter-screens for off target interactions of the compounds and found no off target interactions. Additionally, these compounds block Vpu-mediated modulation of CD4, BST-2/Tetherin and antibody dependent cell-mediated toxicity (ADCC). Unfortunately, both SRI-41897 and SRI-42371 were shown to be specific to the N-terminal region of NL4-3 Vpu and did not function against other, more clinically relevant, strains of Vpu; however, this assay may be slightly modified to include more significant Vpu strains in the future.
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