Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease.

Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A) is known to phosphorylate the microtubule-associated tau protein. Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied. SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC50  = 1.6 nM) and GSK-3ß (IC50  = 10.8 nM) kinase activity. Tau phosphorylation measured in cell-based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC50  = 16 nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose-dependent reduction of transient hypothermia-induced phosphorylated tau in the brains of wild-type mice compared to vehicle (47%, p < 0.001). Long-term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3 mg/kg, QD, for 3 months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau-positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire-hang test compared to vehicle-treated mice (p = 0.048). SM07883, a potent, orally bioavailable, brain-penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD.

Ligands of the neuropeptide Y Y2 receptor.

Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian brain and exerts a variety of physiological processes in humans via four different receptor subtypes Y1, Y2, Y4 and Y5. Y2 receptor is the most abundant Y subtype receptor in the central nervous system and implicated with food intake, bone formation, affective disorders, alcohol and drugs of abuse, epilepsy, pain, and cancer. The lack of small molecule non-peptidic Y2 receptor modulators suitable as in vivo pharmacological tools hampered the progress to uncover the precise pharmacological role of Y2. Only in recent years, several potent, selective and non-peptidic Y2 antagonists have been discovered providing the tools to validate Y2 receptor as a therapeutic target. This Letter reviews Y2 receptor modulators mainly non-peptidic antagonists and their structure-activity relationships.

Discovery of ITX 4520: a highly potent orally bioavailable hepatitis C virus entry inhibitor.

The manuscript reports an identification of a highly potent, orally bioavailable hepatitis C virus entry inhibitor through optimization of a previously reported class of molecules (1) that were not stable in the rat plasma. Compound 39 (ITX 4520) exhibited an excellent PK profile in both rats and dogs with good oral exposure, half-life and oral bioavailability. The compound is also well-tolerated in the preliminary in vivo toxicity studies and has been selected as a pre-clinical candidate for our HCV clinical pipeline.

Synthesis and SAR of selective small molecule neuropeptide Y Y2 receptor antagonists.

Highly potent and selective small molecule neuropeptide Y Y2 receptor antagonists are reported. The systematic SAR exploration of a hit molecule N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide, identified from HTS, led to the discovery of highly potent NPY Y2 antagonists 16 (CYM 9484) and 54 (CYM 9552) with IC(50) values of 19 nM and 12 nM respectively.

Discovery of highly potent small molecule Hepatitis C Virus entry inhibitors.

Novel, highly potent small molecule HCV entry inhibitors are reported. The SAR exploration of a hit molecule identified from screening of a compound library led to the identification of highly potent compounds with IC(50) values of <5 nM in the tissue culture HCV infectious assay.