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OXADIAZOLYLTHIOPHENE DERIVATIVES USEFUL AS HISTONE DEACETYLASE INHIBITORS

A compound of Formula I : (I) or a pharmaceutically acceptable salt thereof, wherein: each R’ is QR1; each Q is independently selected from a bond, -C1-C10 alkylene, -C2-C10 alkenylene, -C(O)-, -C(O)O-, -C(O)N(R1)-, -C(O)N(R1)SO2- -N(R1)C(O)-, – N(R1)-, -N(SO2(R1)), -N(R1)SO2- -C(O)NR4R5-, -N(R4R5)C(O)-, -N(R4R5)- – S-, -SO-, -SO2-, -S(O)O-, -SO2N(R1)- and -O-; each R1 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 haloalkyl, C1-C10 heteroalkyl, aryl, heteroaryl, C3-C10 cycloalkyl, -(C1-C10 alkylene)-C3-C10 cycloalkyl, halogen, cyano, C1-C10 alkylene- aryl, C1-C10 alkylene heteroaryl, C1-C10 heterocycloalkyl and -(C1-C10 alkylene)- C1-C10 heterocycloalkyl. The compounds are inhibitors of HDAC and therefore have potential utility in the therapy of a number of conditions including cancer and inflammation.

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TETRAHYDROPYRAN-BASED THIODISACCHARIDE MIMICS AS GALECTIN-3 INHIBITORS

The present disclosure relates to compounds of Formula (1), which inhibit Gal-3, and include pharmaceutically acceptable salts, compositions comprising such compounds, and methods making and using such compounds and compositions.

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TREATMENT OF OCULAR DISORDERS

The invention provides methods of treatment of ocular disorders, including ocular disease with an angiogenic component. In certain embodiments, the treatment comprises administration of a ROCK2 inhibitor and an angiogenesis inhibitor. In certain embodiments, the ROCK2 inhibitor is ROCK2 selective. In certain embodiments, the angiogenesis inhibitor is a VEGF antagonist, for example, and VEGFR2 antibody.

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Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures

Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 A resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.

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Chemistry, like all the natural sciences, begins with the direct observation of nature¡ª in this case, of matter. SDS of cas: 39093-93-1, The former is the study of compounds containing at least one carbon-hydrogen bonds.In a patent£¬Which mentioned a new discovery about 39093-93-1

Synthesis & Biological Activity of Some New Carboxamides, Carbohydrazides & Carbamates Derived from 2,3-Dihydro-5(H)-oxothiazolo<3,2-a>pyrimidine-6-carboxylic Acid

Some new carboxamides (Va-j), carbohydrazides (Vk-p) and carbamates (VIIIa-d) derived from 2,3-dihydro-5(H)-oxothiazolo<3,2-a>pyrimidine-6-carboxylic acid (III) have been synthesised and evaluated for their antiinflammatory, antibacterial, antifungal and anthelmintic activities.The carboxamides (Ve,i,j) and carbohydrazides (Vk,n,o) possess promising antiinflammatory activity against carrageenin-induced paw oedema in rats, compound Ve being the most active member of the series showing 50.8 percent inhibition at 200 mg/kg (p.o.) dose.Ve, however, is found to be inactive at lower doses.None of the compounds shows any noteworthy antibacterial, antifungal or anthelmintic activities except Vk which displays promising antitubercular activity in vitro (MIC=5 mcg/ml) against Mycobacterium tuberculosis H37Rv.

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SUBSTITUTED PYRROLIDINE-2-CARBOXAMIDES

There are provided compounds of the formula wherein X, Y, Z, R1, R2, R3 and R4 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.

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Piperidine and piperazine inhibitors of fatty acid amide hydrolase targeting excitotoxic pathology

FAAH inhibitors offer safety advantages by augmenting the anandamide levels ?on demand? to promote neuroprotective mechanisms without the adverse psychotropic effects usually seen with direct and chronic activation of the CB1 receptor. FAAH is an enzyme implicated in the hydrolysis of the endocannabinoid N-arachidonoylethanolamine (AEA), which is a partial agonist of the CB1 receptor. Herein, we report the discovery of a new series of highly potent and selective carbamate FAAH inhibitors and their evaluation for neuroprotection. The new inhibitors showed potent nanomolar inhibitory activity against human recombinant and purified rat FAAH, were selective (>1000-fold) against serine hydrolases MGL and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Evaluation of FAAH inhibitors 9 and 31 using the in vitro competitive activity-based protein profiling (ABPP) assay confirmed that both inhibitors were highly selective for FAAH in the brain, since none of the other FP-reactive serine hydrolases in this tissue were inhibited by these agents. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on known FAAH cocrystal structures. To rationally design new molecules that are irreversibly bound to FAAH, we have constructed ?precovalent? FAAH-ligand complexes to identify good binding geometries of the ligands within the binding pocket of FAAH and then calculated covalent docking poses to select compounds for synthesis. FAAH inhibitors 9 and 31 were evaluated for neuroprotection in rat hippocampal slice cultures. In the brain tissue, both inhibitors displayed protection against synaptic deterioration produced by kainic acid-induced excitotoxicity. Thus, the resultant compounds produced through rational design are providing early leads for developing therapeutics against seizure-related damage associated with a variety of disorders.

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Hi-JAK-ing the ubiquitin system: The design and physicochemical optimisation of JAK PROTACs

PROTACs have recently emerged as a novel paradigm in drug discovery. They can hijack existing biological machinery to selectively degrade proteins of interest, in a catalytic fashion. Here we describe the design, optimisation and biological activity of a set of novel PROTACs targeting the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) of proximal membrane-bound proteins. The JAK family proteins display membrane localisation by virtue of their association with cytoplasmic tails of cytokine receptors, and there are no reports of a successful PROTAC strategy being deployed against this class of proteins. JAK PROTACs from two distinct JAK chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing JAK1 and JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets. A number of known ligase binders were explored, and it was found that PROTACs bearing an inhibitor of apoptosis protein (IAP) ligand induced significantly more JAK degradation over Von Hippel?Lindau (VHL) and Cereblon (CRBN) PROTACs. In addition, the mechanism of action of the JAK PROTACs was elucidated, and it was confirmed that JAK degradation was both IAP- and proteasome-dependent.

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HETEROCYCLIC COMPOUNDS, MEDICAMENTS CONTAINING THEM, USE AND PROCESSES FOR THE PREPARATION THEREOF

The present invention relates to compounds of general formula (I) and the tautomers and 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, and the use thereof for the treatment of diseases, particularly diseases of the lungs and airways.

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(R)-3-(N,N-DIMETHYLAMINO)PYRROLIDINE DERIVATIVES

(R)-3-(N,N-Dimethyiamino)pyrrolidine derivatives of formula (I), wherein the meaning for Cy1 is as disclosed in the description. These compounds are useful as JAK3 kinase inhibitors

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