Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.

Background And Objectives: HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870.

Methods: The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal).

Design, synthesis and evaluation of novel monoamine oxidase B (MAO-B) inhibitors with improved pharmacokinetic properties for Parkinson's disease.

A series of novel ((benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide derivatives were designed, synthesized and evaluated as MAO-B inhibitors. SAR studies indicated that cyclizing benzyl ether into benzofuran ring resulted in the most potent MAO-B inhibitor (IC = 0.037 μM), (2S,4S)-4-fluoro-1-((2-(4-fluorophenyl) benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide (C14).

Deciphering Nonbioavailable Substructures Improves the Bioavailability of Antidepressants by Serotonin Transporter.

Inadequate bioavailability is one of the most critical reasons for the failure of oral drug development. However, the way that substructures affect bioavailability remains largely unknown. Serotonin transporter (SERT) inhibitors are first-line drugs for major depression disorder, and improving their bioavailability may be able to decrease side-effects by reducing daily dose.

Novel difluoromethylated 1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT receptor antagonist with AMDE-improving properties: Design, synthesis, and biological evaluation.

Serotonin type 6 receptor (5-HTR) has been considered as a particularly promising target for treating cognitive deficits due to the positive effects of its antagonists in a wide range of memory impairment paradigms. In this study, we designed, synthesized, and evaluated a series of 3-(difluoromethyl)-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HTR antagonists. Structure-activity relationship study led to the discovery of five compounds (6a, 6m, 6n, 6p and 6q) with potent binding affinity at 5-HTR.

Novel difluoromethyl-containing 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)-1H-indole scaffold as potent 5-HTR antagonists: Design, synthesis, biological evaluation, and early in vivo cognition-enhancing studies.

Herein, a series of novel 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)- 1H-indole derivatives were designed and synthesized via hybridization strategy of idalopirdine and SB-271046. The optimal compound C14 (K = 0.085 nM), with difluoromethyl on C3 position on indole scaffold, increased the affinity for the 5-HTR up to 10-folds than idalopirdine (K = 0.

Pd(II)-Catalyzed Synthesis of Alicyclic[]-Fused Pyridines via C(sp)-H Activation of -Unsaturated -Acetyl Hydrazones with Vinyl Azides.

A new synthetic protocol for alicyclic[]-fused pyridines with complete regioselectivity from unsaturated -acetyl hydrazones and vinyl azides via Pd(II)-catalyzed C-H activation/cyclization/aromatization strategy has been described. A series of five- to eight-membered alicyclic[]-fused pyridines were prepared in a one-step manner with wide substrate scope and good functional group tolerance.

Enhancing monoamine oxidase B inhibitory activity via chiral fluorination: Structure-activity relationship, biological evaluation, and molecular docking study.

Parkinson's disease (PD) is a common neurodegenerative disease among the elderly. Currently, monoamine oxidase B (MAO-B) inhibitors are extensively used for PD in clinics. In this work, a series of novel chiral fluorinated pyrrolidine derivatives were designed and synthesized.

Design, synthesis and biological evaluation of pyridinylmethylenepiperidine derivatives as potent 5-HT receptor agonists for migraine therapy.

Migraine is a common neurovascular disease which has been classified as the sixth most disabling disorder. Current migraine therapy was triptans, however, riptans can cause contraction of blood vessels. Therefore, novel drugs without cardiovascular effects emerged, such as CGRP and selective 5-HT receptor agonists.

Synthesis and biological evaluation of 1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives as potential SSRIs.

A series of novel 1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives were synthesized and evaluated for their serotonin (5-HT) reuptake inhibitory activity. The results in vitro indicated that most of the evaluated compounds displayed potent 5-HT reuptake inhibition. The most promising compound A20 was stable in human liver microsomes and possessed good pharmacokinetic properties.

Computational Fragment-Based Design Facilitates Discovery of Potent and Selective Monoamine Oxidase-B (MAO-B) Inhibitor.

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD.

Synthesis and biological evaluation of novel (thio)urea derivatives as potential antitumor agents.

A series of novel (thio)ureas containing the pyrimidinyl group was designed and synthesized. Their in-vitro antitumor activity against different human tumor cells was examined. Some of the compounds showed potential antitumor activity, which provided some hints for further studies on structure modification.

Synthesis and antitumor activity of novel chalcone derivatives.

A novel series of chalcone derivatives containing pyrimidinyl group were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines. Most of the prepared compounds showed potential cytotoxicity against several human cancer cell lines. The compound 5g displayed more potent cytotoxic activities against human cancer cell lines in comparison with Curcumin.

Synthesis and antitumor activity of ureas containing pyrimidinyl group.

A novel series of ureas containing pyrimidinyl group were designed and synthesized. Some of the prepared compounds showed potential cytotoxicity against several human cancer cell lines. From the structure-activity relationships we may conclude that introduction of a sulfide bridge between phenyl and pyrimidinyl rings would be critical for their biological activities.