Synthesis and evaluation of multi-functional NO-donor/insulin-secretagogue derivatives for the treatment of type II diabetes and its cardiovascular complications

Although there is a significant effort in the discovery of effective therapies to contrast both the pathological endocrine and metabolic aspects of diabetes and the endothelial dysfunction associated with this disease, no hypoglycemic drug has been proven to defeat the cardiovascular complications associated with type II diabetes. The aim of this research was to design new compounds exhibiting a double profile of hypoglycemic agents/NO-donors. The synthesis of molecules obtained by the conjunction of NO-donor moieties with two oral insulin-secretagogue drugs (repaglinide and nateglinide) was reported. NO-mediated vasorelaxing effects of the synthesized compounds were evaluated by functional tests on isolated endothelium-denuded rat aortic rings. The most potent molecule (4) was tested to evaluate the hypoglycemic and the anti-ischemic cardioprotective activities. This study indicates that 4 should represent a new insulin-secretagogue/NO-donor prodrug with an enhanced cardiovascular activity, which may contrast the pathological aspects of diabetes and endowed of cardioprotective activity

Novel Transthyretin Amyloid Fibril Formation Inhibitors: Synthesis, Biological Evaluation, and X-Ray Structural Analysis

Transthyretin (TTR) is one of thirty non-homologous proteins whose misfolding, dissociation, aggregation, and deposition is linked to human amyloid diseases. Previous studies have identified that TTR amyloidogenesis can be inhibited through stabilization of the native tetramer state by small molecule binding to the thyroid hormone sites of TTR. We have evaluated a new series of β-aminoxypropionic acids (compounds 5–21), with a single aromatic moiety (aryl or fluorenyl) linked through a flexible oxime tether to a carboxylic acid. These compounds are structurally distinct from the native ligand thyroxine and typical halogenated biaryl NSAID-like inhibitors to avoid off-target hormonal or anti-inflammatory activity. Based on an in vitro fibril formation assay, five of these compounds showed significant inhibition of TTR amyloidogenesis, with two fluorenyl compounds displaying inhibitor efficacy comparable to the well-known TTR inhibitor diflunisal. Fluorenyl 15 is the most potent compound in this series and importantly does not show off-target anti-inflammatory activity. Crystal structures of the TTR∶inhibitor complexes, in agreement with molecular docking studies, revealed that the aromatic moiety, linked to the sp(2)-hybridized oxime carbon, specifically directed the ligand in either a forward or reverse binding mode. Compared to the aryl family members, the bulkier fluorenyl analogs achieved more extensive interactions with the binding pockets of TTR and demonstrated better inhibitory activity in the fibril formation assay. Preliminary optimization efforts are described that focused on replacement of the C-terminal acid in both the aryl and fluorenyl series (compounds 22–32). The compounds presented here constitute a new class of TTR inhibitors that may hold promise in treating amyloid diseases associated with TTR misfolding

Antiherpes virus agents: A review

A review with 33 refs. In this review, after some considerations about the structure of the virus and the viral replicative cycle, herpes virus diseases in man are described. The most important antiherpes virus drugs until now discovered are then reported analyzing and examg. their chem. structure related to their mechanism of action and their pharmacol. activity. Finally, defects of antiherpes virus drugs currently in therapy are shown, in order to outline which directions future developments will have to follow

Synthesis and pharmacological activity of 1-phenyl-2-oxa-5-azabicyclo[4.4.0]decane derivatives

Title compds. I (Z = O, H2; R = H, Me) and II were prepd., and they showed central nervous system stimulant and anticonvulsant activity. Thus, a 2-aminocyclohexanol deriv. was treated with ClCH2COCl and NaOH to give amide III, and III and KOCMe3 in C6H6 were kept at room temp. to give I (Z = O, R = H)

4-ARYLPIPERIDINE DERIVATIVES AND USE THEREOF FOR PREPARING A MEDICAMENT FOR THE TREATMENT OF CNS DISEASE

Title compds. [I; R1 = H, (unsatd.) alkyl; X = O, S, N; R2 = (CH2)nY; n = 1-4; Y, Ar = substituted aryl], were prepd. Thus, 4-(4-fluorophenyl)-4-[(4-trifluoromethyl)benzyloxy]piperidine hydrochloride (prepn. from 4-bromofluorobenzene, N-benzyl-4-piperidone, and 4-trifluoromethylbenzyl bromide given) bound to serotonin transporter in rat frontal cortex membranes with Ki = 26.8 pM; binding to dopamine transporter was negligible