Design, Synthesis, and Development of pyrazolo[1,5-]pyrimidine Derivatives as a Novel Series of Selective PI3K Inhibitors: Part I-Indole Derivatives.

Phosphoinositide 3-kinase (PI3K), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5-]pyrimidine with IC values in the low nanomolar range and high selectivity against the PI3K isoform.

Design, Synthesis, and Development of Pyrazolo[1,5-]pyrimidine Derivatives as a Novel Series of Selective PI3K Inhibitors: Part II-Benzimidazole Derivatives.

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: , , , ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3K, displaying IC values ranging from 1.

Esketamine inhaled as dry powder: Pharmacokinetic, pharmacodynamic and safety assessment in a preclinical study.

Ketamine and its enantiomer esketamine have gained much attention in recent years as potent, fast-acting agents for the management of treatment-resistant depression. However, an alternative to oral ketamine administration is required to ensure adequate systemic exposure as the drug undergoes extensive first-pass metabolism. We propose dry powder inhalation as a new esketamine delivery route.

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.

GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI).

Discovery and development of CPL207280 as new GPR40/FFA1 agonist.

Due to a unique mechanism that limits the possibility of hypoglycemia, the free fatty acid receptor (FFA1) is an attractive target for the treatment of type 2 diabetes. So far, however, none of the promising agonists have been able to enter the market. The most advanced clinical candidate, TAK-875, was withdrawn from phase III clinical trials due to liver safety issues.

CPL207280, a Novel G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1-Specific Agonist, Shows a Favorable Safety Profile and Exerts Antidiabetic Effects in Type 2 Diabetic Animals.

G protein-coupled receptor (GPR) 40 is a free fatty acid receptor mainly expressed in pancreatic -cells activated by medium- and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca]). Activation of GPR40 in pancreatic -cells may improve glycemic control in type 2 diabetes through enhancement of glucose-stimulated insulin secretion. However, the most clinically advanced GPR40 agonist-TAK-875 (fasiglifam)-was withdrawn from phase III because of its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters.

Unexpected role of O-2 "protecting" groups of glycosyl donors in mediating regioselective glycosidation.

Glycosidation of several vicinal diols reveals that exquisite regioselectivity can be achieved by using 2-O-benzoyl n-pentenyl glycoside donors and/or their cyclic 1,2-ortho ester counterparts. The regioselective preferences for both are the same, although ratios and yields may differ. In stark contrast, glycosidation of the diols with the corresponding 2-O-benzylated donors gives poor, if any, regioselectivity.