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Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).

The present application relates to a pyrazolopyrimidine compound of Formula (I) and a pharmaceutically acceptable salt thereof. Such compounds can be used to inhibit the activity of a lipid kinase PI3K, and can also be used to treat diseases mediated by P

Background: The 2-alkynyl pyrazolo[1,5-a]pyrimidine derivatives have been explored as new and potential anti-proliferative agents. Methods: Ultrasound assisted synthesis of these compounds was carried out by using a multi-step method involving the H3PO3 mediated construction of pyrazolo[1,5-a]pyrimidine ring possessing a bromo group at C-2 position followed by Pd/C-Cu catalyzed alkynylation methodology as the key steps. Results and Conclusion: All these compounds showed selective growth inhibition of cancer cell lines when tested against MDA-MB 231 and K562 cell lines along with non-cancerous HEK293 cells.

New series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with KIs of 2.5-102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO2substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO2group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively.

New heteroarylcarboxamide head groups substituted with two aromatic rings analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase with various level of selectivity for c-Met RTK were obtained.

Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation

Pyranones fused with a pyrazolopyrimidine moiety were prepared via regioselective construction of pyranone ring using (Pd/C-mediated)coupling- iodocyclization followed by Sonogashira/Heck/Suzuki reactions. The pyrazolopyrimidine based reactant required was obtained via a new H 3PO3 mediated condensation reaction. This strategy has led to the discovery of a novel and potentially safe PDE4 inhibitor.

In the present study, a novel series of Pyrazole derivatives (3a-m) were synthesized by condensing ethyl-3-(dimethylamino)-2-(phenylcarbonyl)prop-2- enoate with different aromatic and aliphatic hydrazines. These newly synthesized compounds were characteri

11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.

The invention relates to novel phenethylamide derivatives and their heterocyclic analogues of formula (I), wherein A, B, R1, R2 and R3 are as described in the application, and to the use of such compounds, or of pharmaceut

The present invention relates to a compound represented by the formula:( I ) wherein ring A is a 5- or 6-membered aromatic heterocycle optionally having substituent (s); U, V and W are each independently C or N, provided that when any one of U, V and W is N, then the others should be C; Ra and Rb are each independently a cyclic group optionally having substituent (s), a C1-10 alkyl group optionally having substituent (s), a C2-10 alkenyl group optionally having substituent (s), or a C2-10alkynyl group optionally having substituent (s); X is a bond, or a spacer having 1 to 6 atoms in the main chain; Y is a spacer having 1 to 6 atoms in the main chain; Rc is a hydrocarbon group optionally containing heteroatom(s) as the constituting atom(s), which optionally has substituent (s); m and n are each independently 1 or 2; and ring B optionally further has substituent (s), or a salt thereof. The compound of the present invention has excellent renin inhibitory activity, and thus is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension, and the like.

The present invention relates to the orexin receptor antagonists of the general formula (I), which are selective to orexin I receptors. (I)-wherein Ar stands for phenyl group or a 5- or 6-membered heterocyclic ring containing 1-3 identical or different he

A number of 5-aryl-1-[4-(methylsulfonyl)-phenyl]-1H-pyrazoles and 4-(5-aryl-1H-pyrazol-1-yl)benzenesulfonamides 3, 4, 5, 6, analogues of the COX-2 selective inhibitor celecoxib (celebrex), were synthesized. In order to verify the effects on the biological properties of certain substituents put on position 4 of the pyrazole nucleus, some of these compounds were screened in vivo for their anti-inflammatory and analgesic activities. Moreover, sodium salts of carboxylic acids 4 were tested in vitro for their platelet anti-aggregating properties. The results of these preliminary biological assays showed that new derivatives are not endowed with improved anti-inflammatory and analgesic properties, in comparison with celecoxib. In addition, docking studies were carried out on the most significative compounds to evaluate their interaction mode at the active site of both COX-1 and COX-2. Some remarks about the SAR of this class of COX-inhibitors are drown out.

A new application of the hypervalent iodine reagent phenyliodine(III)bis(trifluoroacetate) (PIFA) has been developed for the construction of a series of N, O, S-containing heterocycle-fused quinolinone derivatives in a general and efficient way. An altern

Ethyl 2-benzoyl-3-dimethylaminopropenoate (6) and methyl 2-benzoylamino-3-dimethylaminopropenoate (46) were used as reagents for the protection of the amino group with 2-benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxycarbonylvinyl groups in t

5,6-Disubstituted 3-benzoylamino-2H-pyran-2-ones 3 are prepared either from 1.3-dicarbonyl compounds 1 and methyl 2-benzoyl-amino-3-dimethylaminopropenoate (2) in an one-step reaction or from ethyl 2-acyl-3-dimethylaminopropenoates 5a,b or 2-(dimethylamino)-methylene-1,3-diketones 5c,d and 5-oxo-2-phenyl-1,3-oxazole 6.

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We wish to report an improved, general synthesis of 4-aryl-5-pyrimidinecarboxylates 1.Two different routes have previously been reported for the synthesis of examples of this class of pyrimidine carboxylates.The parent compound, ethyl 4-phenyl-5-pyrimidinecarboxylate was prepared in low yield by the reaction of s-triazine with ethyl benzoyl acetate.In addition, the enol ether β-ketoaldehyde synthon, ethyl 2-benzoyl-3-ethoxy-2-propenoate, was reported to give 1a in modest yield when reacted with guanidine (2).