35888-99-4Relevant articles and documents
Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists
Van Veldhoven, Jacobus P.D.,Liu, Rongfang,Thee, Stephanie A.,Wouters, Yessica,Verhoork, Sanne J.M.,Mooiman, Christiaan,Louvel, Julien,Ijzerman, Adriaan P.
, p. 4013 - 4025 (2015)
Structure-affinity relationship (SAR) and structure-kinetics relationship (SKR) studies were combined to investigate a series of biphenyl anthranilic acid agonists for the HCA2 receptor. In total, 27 compounds were synthesized and twelve of them showed higher affinity than nicotinic acid. Two compounds, 6g (IC50 = 75 nM) and 6z (IC50 = 108 nM) showed a longer residence time profile compared to nicotinic acid, exemplified by their kinetic rate index (KRI) values of 1.31 and 1.23, respectively. The SAR study resulted in the novel 2-F, 4-OH derivative (6x) with an IC50 value of 23 nM as the highest affinity HCA2 agonist of the biphenyl series, although it showed a similar residence time as nicotinic acid. The SAR and SKR data suggest that an early compound selection based on binding kinetics is a promising addition to the lead optimization process.
Site-Selective, Remote sp3 C?H Carboxylation Enabled by the Merger of Photoredox and Nickel Catalysis
Sahoo, Basudev,Bellotti, Peter,Juliá-Hernández, Francisco,Meng, Qing-Yuan,Crespi, Stefano,K?nig, Burkhard,Martin, Ruben
supporting information, p. 9001 - 9005 (2019/06/24)
A photoinduced carboxylation of alkyl halides with CO2 at remote sp3 C?H sites enabled by the merger of photoredox and Ni catalysis is described. This protocol features a predictable reactivity and site selectivity that can be modulated by the ligand backbone. Preliminary studies reinforce a rationale based on a dynamic displacement of the catalyst throughout the alkyl side chain.
A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of Aryl Olefins with Pd and Formic Acid
Liu, Wei,Ren, Wenlong,Li, Jingfu,Shi, Yuan,Chang, Wenju,Shi, Yian
supporting information, p. 1748 - 1751 (2017/04/11)
An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac2O and formic acid is described. A variety of 2- and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas.
Pd-Catalyzed β-C(sp3)?H Arylation of Propionic Acid and Related Aliphatic Acids
Ghosh, Kiron K.,van Gemmeren, Manuel
supporting information, p. 17697 - 17700 (2017/12/07)
A generally applicable Pd-catalyzed protocol for the β-C(sp3)?H arylation of propionic acid and related α-branched aliphatic acids is reported. Enabled by the use of N-acetyl-β-alanine as ligand our protocol delivers a broad range of arylation products. Notably, the highly challenging substrate, propionic acid, which lacks any acceleration through the Thorpe–Ingold effect, can be employed as substrate with synthetically useful yields. Furthermore, the scalability and synthetic applicability of the protocol are demonstrated.
Structure-activity relationship of a new series of reversible dual monoacylglycerol lipase/fatty acid amide hydrolase inhibitors
Cisneros, José A.,Bj?rklund, Emmelie,González-Gil, Inés,Hu, Yanling,Canales, ángeles,Medrano, Francisco J.,Romero, Antonio,Ortega-Gutiérrez, Silvia,Fowler, Christopher J.,López-Rodríguez, María L.
supporting information; experimental part, p. 824 - 836 (2012/04/10)
The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (±)-oxiran-2-ylmethyl 6-(1,1′-biphenyl-4-yl)hexanoate (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC50 (8) = 4.1 μM; IC 50 (30) = 2.4 μM), rat brain monoacylglycerol hydrolysis (IC 50 (8) = 1.8 μM; IC50 (30) = 0.68 μM), and rat brain FAAH (IC50 (8) = 5.1 μM; IC50 (30) = 0.29 μM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or noncompetitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.
Discovery of novel Tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats
Shen, Hong C.,Ding,Deng, Qiaolin,Wilsie, Larissa C.,Krsmanovic, Mihajlo L.,Taggart, Andrew K.,Carballo-Jane, Ester,Ren, Ning,Cai,Wu,Wu, Kenneth K.,Cheng, Kang,Chen, Qing,Wolff, Michael S.,Tong, Xinchun,Holt, Tom G.,Waters, M. Gerard,Hammond, Milton L.,Tata, James R.,Colletti, Steven L.
supporting information; experimental part, p. 2587 - 2602 (2010/01/15)
Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were di
TETRACYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE
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Page/Page column 38, (2009/01/20)
Certain tetracyclic compounds are described, which may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).
NIACIN RECEPTOR AGONISTS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT
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Page/Page column 25; 34-35, (2008/06/13)
The present invention encompasses compounds of Formula (I) as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating atherosclerosis, dysliptdemias and the like. Pharmaceutical compositions and methods of use are also
Structure-activity relationships of α-ketooxazole inhibitors of fatty acid amide hydrolase
Hardouin, Christophe,Kelso, Michael J.,Romero, F. Anthony,Rayl, Thomas J.,Leung, Donmienne,Hwang, Inkyu,Cravatt, Benjamin F.,Boger, Dale L.
, p. 3359 - 3368 (2008/02/13)
A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, K, - 2.6 nM), with 5hh (aryl -3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor
Shen, Hong C.,Ding, Fa-Xiang,Luell, Silvi,Forrest, Michael J.,Carballo-Jane, Ester,Wu, Kenneth K.,Wu, Tsuei-Ju,Cheng, Kang,Wilsie, Larissa C.,Krsmanovic, Mihajlo L.,Taggart, Andrew K.,Ren, Ning,Cai, Tian-Quan,Deng, Qiaolin,Chen, Qing,Wang, Junying,Wolff, Michael S.,Tong, Xinchun,Holt, Tom G.,Waters, M. Gerard,Hammond, Milton L.,Tata, James R.,Colletti, Steven L.
, p. 6303 - 6306 (2008/04/12)
Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintainin
