ABSTRACT
Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.
Subject(s)
Enzyme Precursors , Matrix Metalloproteinase 9 , Matrix Metalloproteinase 9/metabolism , Enzyme Precursors/metabolism , Extracellular Matrix/metabolism , Indoles/pharmacology , Indoles/metabolism , Metalloendopeptidases/metabolism , Matrix Metalloproteinase InhibitorsABSTRACT
Orexins play an important role in sleep/wake regulation, and orexin receptor antagonists are a focus of novel therapy for the treatment of insomnia. We identified 27e (TASP0428980) as a potent dual orexin receptor antagonist through the systematic modification of our original designed lead A. We demonstrated the potent sleep-promoting effects of 27e at ip dose of 3mg/kg in a rat polysomnogram study. 27e exhibited relatively short half-life profiles in rats and dogs. Furthermore, accumulating evidence regarding ADME profiles indicates that the predicted human half-life of 27e should be 1.2-1.4h. These data indicated that 27e has a short-acting hypnotic property, suggesting that 27e might be useful for treating primary insomnia while exhibiting a low risk of next-day residual somnolence. Thus, 27e and its related compounds should be further evaluated to enable advancement to clinical trials.
Subject(s)
Benzamides/pharmacology , Drug Discovery , Orexin Receptor Antagonists , Triazoles/pharmacology , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , CHO Cells , Cricetulus , Dogs , Dose-Response Relationship, Drug , Humans , Male , Molecular Structure , Rats , Rats, Wistar , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 antagonists bearing a methylene linker between the isoquinoline and benzamide moieties were described. Optimization focusing on the substituents of the benzamide portion in the right hand part of the molecule led to the identification of TASP0412098 (9l), which is a potent, selective CRTH2 antagonist (binding affinity: IC50=2.1 nM, functional activity: IC50=12 nM). Compound 9l, which was orally bioavailable in mice and guinea pigs, showed in vivo efficacy after oral administration in a bronchial asthma model of guinea pigs.
Subject(s)
Isoquinolines/chemistry , Isoquinolines/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Animals , Cell Line , Dose-Response Relationship, Drug , Guinea Pigs , Humans , Isoquinolines/blood , Male , Mice , Mice, Inbred Strains , Molecular Structure , Structure-Activity Relationship , Th2 CellsABSTRACT
In this study, we describe the synthesis and structure-activity relationship (SAR) of a series of isoquinoline chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50=19 nM) in addition to the excellent functional antagonist activity (IC50=13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50=23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 µM) or the enzymes COX-1 and COX-2 (IC50 >10 µM).
Subject(s)
Drug Design , Isoquinolines/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Th2 CellsABSTRACT
Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 µM) and COX-1 and COX-2 enzymes (IC(50)>10 µM).