- Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase
-
Heme-regulated inhibitor kinase (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, and adaptation to cytoplasmic stress. HRI is also a critical modifier of hemoglobin disorders such as β-thalassemia. We previously identified N,N′-diarylureas as potent activators of HRI suitable for studying the biology of this important kinase. To expand the repertoire of chemotypes that activate HRI, we screened a ~1900 member N,N′-disubstituted urea library in the surrogate eIF2α phosphorylation assay, identifying N-aryl,N′-cyclohexylphenoxyurea as a promising scaffold. We validated hit compounds as a bona fide HRI activators in secondary assays and explored the contributions of substitutions on the N-aryl and N′-cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogues. We tested these N-aryl,N′- cyclohexylphenoxyureas in the surrogate eIF2α phosphorylation and cell proliferation assays, demonstrating significantly improved bioactivities and specificities. We consider these compounds to represent lead candidates for the development of potent and specific HRI activators.
- Chen, Ting,Takrouri, Khuloud,Hee-Hwang, Sung,Rana, Sandeep,Yefidoff-Freedman, Revital,Halperin, Jose,Natarajan, Amarnath,Morisseau, Christophe,Hammock, Bruce,Chorev, Michael,Aktas, Bertal H.
-
-
Read Online
- Inhibition of serine and proline racemases by substrate-product analogues
-
d-Amino acids can play important roles as specific biosynthetic building blocks required by organisms or act as regulatory molecules. Consequently, amino acid racemases that catalyze the formation of d-amino acids are potential therapeutic targets. Serine racemase catalyzes the reversible formation of d-serine (a modulator of neurotransmission) from l-serine, while proline racemase (an essential enzymatic and mitogenic protein in trypanosomes) catalyzes the reversible conversion of l-proline to d-proline. We show the substrate-product analogue α-(hydroxymethyl)serine is a modest, linear mixed-type inhibitor of serine racemase from Schizosaccharomyces pombe (K i = 167 ± 21 mM, Ki′ = 661 ± 81 mM, cf. Km = 19 ± 2 mM). The bicyclic substrate-product analogue of proline, 7-azabicyclo[2.2.1]heptan-7-ium-1-carboxylate is a weak inhibitor of proline racemase from Clostridium sticklandii, giving only 29% inhibition at 142.5 mM. However, the more flexible bicyclic substrate-product analogue tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate is a noncompetitive inhibitor of proline racemase from C. sticklandii (Ki = 111 ± 15 mM, cf. Km = 5.7 ± 0.5 mM). These results suggest that substrate-product analogue inhibitors of racemases may only be effective when the active site is capacious and/or plastic, or when the inhibitor is sufficiently flexible.
- Harty, Matthew,Nagar, Mitesh,Atkinson, Logan,Legay, Christina M.,Derksen, Darren J.,Bearne, Stephen L.
-
-
Read Online
- ALKYNYL QUINAZOLINE COMPOUNDS
-
The present disclosure relates to compounds of Formula (I'): and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans.
- -
-
Paragraph 1094
(2021/02/19)
-
- Trans-Selective and Switchable Arene Hydrogenation of Phenol Derivatives
-
A trans-selective arene hydrogenation of abundant phenol derivatives catalyzed by a commercially available heterogeneous palladium catalyst is reported. The described method tolerates a variety of functional groups and provides access to a broad scope of trans-configurated cyclohexanols as potential building blocks for life sciences and beyond in a one-step procedure. The transformation is strategically important because arene hydrogenation preferentially delivers the opposite cis-isomers. The diastereoselectivity of the phenol hydrogenation can be switched to the cis-isomers by employing rhodium-based catalysts. Moreover, a protocol for the chemoselective hydrogenation of phenols to cyclohexanones was developed.
- Bergander, Klaus,Glorius, Frank,Heusler, Arne,Wollenburg, Marco
-
p. 11365 - 11370
(2020/11/24)
-
- Catalytic Transfer Hydrogenation of Arenes and Heteroarenes
-
Transfer hydrogenation reactions are of great interest to reduce diverse molecules under mild reaction conditions. To date, this type of reaction has only been successfully applied to alkenes, alkynes and polarized unsaturated compounds such as ketones, imines, pyridines, etc. The reduction of benzene derivatives by transfer hydrogenation has never been described, which is likely due to the high energy barrier required to dearomatize these compounds. In this context, we have developed a catalytic transfer hydrogenation reaction for the reduction of benzene derivatives and heteroarenes to form complex 3-dimensional scaffolds bearing various functional groups at room temperature without needing compressed hydrogen gas.
- Gelis, Coralie,Heusler, Arne,Nairoukh, Zackaria,Glorius, Frank
-
supporting information
p. 14090 - 14094
(2020/10/19)
-
- TEAD INHIBITORS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same.
- -
-
Paragraph 00465; 00701
(2020/12/11)
-
- Photoinduced Deoxygenative Borylations of Aliphatic Alcohols
-
A photochemical method for converting aliphatic alcohols into boronic esters is described. Preactivation of the alcohol as a 2-iodophenyl-thionocarbonate enables a novel Barton–McCombie-type radical deoxygenation that proceeds efficiently with visible light irradiation and without the requirement for a photocatalyst, a radical initiator, or tin or silicon hydrides. The resultant alkyl radical is intercepted by bis(catecholato)diboron, furnishing boronic esters from a diverse range of structurally complex alcohols.
- Wu, Jingjing,B?r, Robin M.,Guo, Lin,Noble, Adam,Aggarwal, Varinder K.
-
supporting information
p. 18830 - 18834
(2019/11/22)
-
- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
-
The present disclosure is directed to compounds of Formula (I) and methods of their use and preparation, as well as compositions comprising compounds of Formula (I).
- -
-
Page/Page column 102; 122
(2018/06/30)
-
- UREA DERIVATIVE AND USE THEREFOR
-
The purpose of the present invention is to provide a compound with inhibitory activity on Discoidin Domain Receptor 1. The present invention provides a urea derivative represented by the formula below or a pharmaceutically acceptable salt thereof.
- -
-
Paragraph 0190
(2018/07/29)
-
- Novel Compounds as Autotaxin Inhibitors and Pharmaceutical Compositions Comprising the Same
-
The present invention relates to a novel autotaxin inhibitor compound for preventing and treating disease or symptoms due to an increase in concentration of lysophosphatidic acid or activation of autotaxin. The present invention further relates to a pharmaceutical composition containing the same. The novel compound of the present invention is an autotaxin inhibitor which inhibits production of lysophosphatidic acid, and thus is useful for treating or preventing cardiovascular disease, cancer, metabolic disease, kidney disease, liver disease, inflammatory diseases, nervous disease, respiratory disease, desmoid disease, eye disease, cholestatic symptoms, other types of chronic pruritus or acute, or chronic rejection of transplanted organs.COPYRIGHT KIPO 2017
- -
-
Paragraph 0270-0273
(2018/05/17)
-
- SUBSTITUTED BENZAMIDES AND THEIR USES
-
Provided herein are Substituted Benzamides, compositions, and method of their manufacture and use.
- -
-
Paragraph 0616; 0617
(2015/12/01)
-
- BENZIMIDAZOLYL-METHYL UREA DERIVATIVES AS ALX RECEPTOR AGONISTS
-
The present invention relates to benzimidazolyl-methyl urea derivatives of formula (I), wherein n, D, E, R1, R2, R3, R4, R6, R7, R8 and R9 are as defined in the description, their preparation and their use as pharmaceutically active compounds.
- -
-
Page/Page column 105
(2015/02/25)
-
- 1 -(CYCLOPENT-2-EN-1 -YL)-3-(2-HYDROXY-3-(ARYLSULFONYL)PHENYL)UREA DERIVATIVES AS CXCR2 INHIBITORS
-
The invention relates to 1-(3-sulfonylphenyl)-3-(cyclopent-2-en-1-yl)urea derivatives, and their use in treating or preventing diseases and conditions mediated by the CXCR2 receptor. In addition, the invention relates to compositions containing the derivatives and processes for their preparation.
- -
-
Page/Page column 146; 147
(2015/12/18)
-
- Inhibition of serine and proline racemases by substrate-product analogues
-
d-Amino acids can play important roles as specific biosynthetic building blocks required by organisms or act as regulatory molecules. Consequently, amino acid racemases that catalyze the formation of d-amino acids are potential therapeutic targets. Serine
- Harty, Matthew,Nagar, Mitesh,Atkinson, Logan,Legay, Christina M.,Derksen, Darren J.,Bearne, Stephen L.
-
supporting information
p. 390 - 393
(2015/06/01)
-
- New cyclohexylamine derivatives having beta2 adrenergic agonist and M3 muscarinic antagonist activities
-
The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.
- -
-
Paragraph 0128
(2013/05/23)
-
- NEW CYCLOHEXYLAMINE DERIVATIVES HAVING β2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITIES
-
The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.
- -
-
Page/Page column 39
(2013/05/23)
-
- Cationic spacer arm design strategy for control of antimicrobial activity and conformation of amphiphilic methacrylate random copolymers
-
Antimicrobial and hemolytic activities of amphiphilic random copolymers were modulated by the structure of the cationic side chain spacer arms, including 2-aminoethylene, 4-aminobutylene, and 6-aminohexylene groups. Cationic amphiphilic random copolymers with ethyl methacrylate (EMA) comonomer were prepared with a range of comonomer fractions, and the library of copolymers was screened for antimicrobial and hemolytic activities. Copolymers with 4-aminobutylene cationic side chains showed an order of magnitude enhancement in their antimicrobial activity relative to those with 2-aminoethylene spacer arms, without causing adverse hemolysis. When the spacer arms were further elongated to hexylene, the copolymers displayed potent antimicrobial and hemolytic activities. The 4-aminobutylene side chain appears to be the optimal spacer arm length for maximal antimicrobial potency and minimal hemolysis, when combined with hydrophobic ethylmethacrylate in a roughly 70/30 ratio. The copolymers displayed relatively rapid bactericidal kinetics and broad-spectrum activity against a panel of Gram-positive and Gram-negative bacteria. The effect of the spacer arms on the polymer conformation in the membrane-bound state was investigated by molecular dynamics simulations. The polymer backbones adopt an extended chain conformation, parallel to the membrane surface. A facially amphiphilic conformation at the membrane surface was observed, with the primary ammonium groups localized at the lipid phoshophate region and the nonpolar side chains of EMA comonomers buried in the hydrophobic membrane environment. This study demonstrates that the antimicrobial activity and molecular conformation of amphiphilic methacrylate random copolymers can be modulated by adjustment of cationic side chain spacer arms.
- Palermo, Edmund F.,Vemparala, Satyavani,Kuroda, Kenichi
-
experimental part
p. 1632 - 1641
(2012/09/05)
-
- New cyclohexylamine derivatives having beta2 adrenergic agonist and m3 muscarinic antagonist activities
-
The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.
- -
-
Paragraph 0073
(2013/03/26)
-
- Process for Preparing Azabicyclic Compounds
-
The present invention relates to a process for preparing azabicyclic compounds that are useful intermediates for synthesizing pharmaceutical compounds or salts thereof.
- -
-
Page/Page column 4
(2011/04/18)
-
- SOLID FORMS OF N-(4-(7-AZABICYCLO[2.2.1]HEPTAN-7-YL)-2-TRIFLUOROMETHYL)PHENYL)-4-OXO-5-(TRIFLUOROMETHYL)-1,4-DIHYDROQUINOLINE-3-CARBOXAMIDE
-
The present invention relates to substantially crystalline and solid state forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (Form A-HCl, Form B, Form B-HCl, or any combination of these forms), pharmaceutical compositions thereof, and methods of treatment therewith.
- -
-
Page/Page column 38
(2011/05/06)
-
- A simple and efficient synthesis of N-substituted cyclohex-3-enamines
-
A straightforward preparation of N-substituted cyclohex-3-enamines starting from the commercially available trans-4-aminocyclohexanol hydrochloride is described. Cyclohex-3-enamino-functionalized compounds have proven to be interesting intermediates in me
- Alvarez-Perez, Monica,Marco-Contelles, Jose
-
experimental part
p. 3649 - 3653
(2010/04/05)
-
- BRADYKININ 1 RECEPTOR ANTAGONISTS
-
The invention encompasses novel compounds and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for treatment of diseases mediated by B1 bradykinin receptor.
- -
-
Page/Page column 63
(2008/06/13)
-
- NEW PLEUROMUTILIN DERIVATIVE AND ITS USE
-
The invention is directed to the ethanedisulfonate salt of trans-4-aminocyclohexyl (lS, 2R, 3S, 4S, 6R, 7R, 8R, 14R )-4-ethenyl-3-hydroxy-2,4J7,14-tetramethyl-9- oxotricyclo[5.4.3.01,8]tetradec-6-yl imidodicarbonate (Compound IA.) Compound IA is use for the treatment of a variety of diseases and conditions, such as respiratory tract and skin an skin structure infections. Accordingly, the invention is further directed to pharmaceutical compositions comprising Compound IA. The invention is still further directed to methods of treating respiratory tract and skin and skin structure infections using Compound IA or a pharmaceutical composition comprising Compound IA.
- -
-
Page/Page column 11
(2010/11/27)
-
- Crystalline forms of cis-5-fluoro-N-?4-(2-hydroxy-4-methylbenzamido)cyclohexyl|-2-(tetrahydrothiopyran-4-yloxy)nicotinamide
-
The present invention relates to new crystalline forms of syn-5-Fluoro-N-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-2-(tetrahydro-thiopyran-4-yloxy)-nicotinamide and to processes for the preparation of, compositions containing and the uses of such crystalline forms.
- -
-
Page/Page column 14
(2008/06/13)
-
- Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
-
The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
- -
-
Page/Page column 47
(2010/02/11)
-
- 4-CYCLOALKYLAMINOPYRAZOLO PYRIMIDINE NMDA/NR2B ANTAGONISTS
-
Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are effective as NMDA/NR2B antagonists useful for treating neurological conditions such as, for example, pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain injury including stroke, and other conditions.
- -
-
Page/Page column 18
(2010/02/11)
-
- ANTITHROMBOTIC ETHERS
-
This application relates to a compound of formula I (or a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa and/or thrombin, as well as a process for its preparation and intermediates therefor (I).
- -
-
-
- Conformationally restricted analogs of deoxynegamycin
-
Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC50=8.2μM; 44, IC 50=6.6μM; 35e2, IC50=1μM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16μg/mL; Klebsiella pneumoniae, MIC=8μg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED50=4.8mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules.
- Raju,Anandan, Sampathkumar,Gu, Shihai,Herradura, Prudencio,O'Dowd, Hardwin,Kim, Bum,Gomez, Marcela,Hackbarth, Corinne,Wu, Charlotte,Wang, Wen,Yuan, Zhengyu,White, Richard,Trias, Joaquim,Patel, Dinesh V.
-
p. 3103 - 3107
(2007/10/03)
-
- SUBSTITUTED QUINAZOLINONE COMPOUNDS
-
A variety of low molecular weight, guanidino-containing molecules capable of acting as MC4-R agonists are provided. The compounds are useful in treating MC4-R mediated diseases. The compounds have the structure of Formulas (IA), (IB), or (IC): where the v
- -
-
-
- Total synthesis and absolute configuration of radiosumin, a strong trypsin inhibitor from the blue-green alga Plectonema radiosum
-
Radiosumin (1), a strong trypsin inhibitory dipeptide isolated from the freshwater blue-green alga Plectonema radiosum (NIES-515), was synthesized for the first time by use of the hetero Diels-Alder reaction, the Horner-Wadsworth-Emmons reaction, the Corey-Winter reaction, regioselective hydrogenation, and reduction with zinc and formic acid as key steps, which unambiguously determined the absolute configuration of the structurally unique and biologically intriguing aquatic natural product (1).
- Noguchi, Hirohide,Aoyama, Toyohiko,Shioiri, Takayuki
-
p. 471 - 504
(2007/10/03)
-