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Bioactive Benzofuran derivatives: A review

In nature’s collection of biologically active heterocycles, benzofuran derivatives constitute a major group. The broad spectrum of pharmacological activity in individual benzofurans indicates that this series of compounds is of an undoubted interest. Benzofuran and its derivatives have attracted medicinal chemists and pharmacologists due to their pronounced biological activities and their potential applications as pharmacological agents. Due to the wide range of biological activities of benzofurans, their structure activity relationships have generated interest among medicinal chemists, and this has culminated in the discovery of several lead molecules in numerous disease conditions. The outstanding development of benzofuran derivatives in diverse diseases in very short span of time proves its magnitude for medicinal chemistry research. The present review is endeavour to highlight the progress in the various pharmacological activities of benzofuran derivatives in the current literature with an update of recent research findings on this nucleus.

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Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Nav1.8 (PN3) as well as the Nav1.2 and Nav1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.

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IMIDAZOPYRIDINES AS A NOVEL SCAFFOLD FOR MULTI-TARGETED KINASE INHIBITION

Compounds that inhibit protein kinases, compositions containing the compounds and methods of treating diseases using the compounds are disclosed. Formula (I).

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5-Vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta: Optimization of enzymatic and functional activity

PKCtheta is a serine/threonine kinase involved in the regulation of IL2 production in T cells. It has recently become an attractive therapeutic target for a variety of immunological disorders. We describe the optimization of the enzymatic and cellular potency of a series of 5-vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta. A binding model was developed that explains much of the SAR observed for this series, including the enzymatic potency observed for 19. An analysis of functional potency against various physiochemical parameters suggests that cellular potency is correlated with Log D7.4, but not with c Log P, PAMPA permeability, or TPSA.

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Discovery of a 5 H-benzo[4,5]cyclohepta[1,2-b ]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5] cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.

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AMILORIDE-TYPE COMPOUNDS AS INHIBITORS IN EPITHELIAL SODIUM CHANNELS FOR THE TREATMENT OF DISEASES OF THE LUNGS AND AIRWAYS

P01-2935/FF 88/88 -88- ABSTRACT The present invention relates to compounds of general formula (I) R N NNH 2 N O N H NH 2 NH 2 X A’ A (I) and the tautomersand the salts thereof, particularly the pharmaceutically acceptable salts thereof with inorganic or organic acids and bases, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, the use thereof for the treatmentof diseases, particularly diseases of the lungs and airways.

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Design and synthesis of imidazole and triazole derivatives as Lp-PLA 2 inhibitors and the unexpected discovery of highly potent quaternary ammonium salts

New Lp-PLA2 inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo.

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Fragment-based discovery of 7-azabenzimidazoles as potent, highly selective, and orally active CDK4/6 inhibitors

Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

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Fine tuning of physico-chemical parameters to optimise a new series of novobiocin analogues

A novel series of novobiocin analogues has been synthesised by removing the lipophilic aryl chain in novobiocin and introducing an amino substituent. The structural modifications have been dictated by the control of lipophilicity and the dissociation constant of the resulting compounds. Antibacterial activity of the new coumarin derivatives could be correlated with the amount of uncharged form in physiological conditions.

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PHARMACEUTICALLY ACTIVE PYRAZOLO-TRIAZINE AND/OR PYRAZOLO-PYRIMIDINE DERIVATIVES

The present invention relates to pyrazolo [1,5 -a] [1,3,5 ]triazine and pyrazolo[1,5-a] pyrimidine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases and infectious diseases. Furthermore, the present invention is directed towards pharmaceutical compositions containing at least one of the pyrazo lo [1,5-a][1,3,5 ]triazine and pyrazolo [1,5-a]pyrimidine derivatives and/or pharmaceutically acceptable salts thereof.

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