6023-70-7Relevant academic research and scientific papers
Orthogonal Regulation of Nucleophilic and Electrophilic Sites in Pd-Catalyzed Regiodivergent Couplings between Indazoles and Isoprene
Jiang, Wen-Shuang,Ji, Ding-Wei,Zhang, Wei-Song,Zhang, Gong,Min, Xiang-Ting,Hu, Yan-Cheng,Jiang, Xu-Liang,Chen, Qing-An
supporting information, p. 8321 - 8328 (2021/03/16)
Depending on the reactant property and reaction mechanism, one major regioisomer can be favored in a reaction that involves multiple active sites. Herein, an orthogonal regulation of nucleophilic and electrophilic sites in the regiodivergent hydroamination of isoprene with indazoles is demonstrated. Under Pd-hydride catalysis, the 1,2- or 4,3-insertion pathway with respect to the electrophilic sites on isoprene could be controlled by the choice of ligands. In terms of the nucleophilic sites on indazoles, the reaction occurs at either the N1- or N2-position of indazoles is governed by the acid co-catalysts. Preliminary experimental studies have been performed to rationalize the mechanism and regioselectivity. This study not only contributes a practical tool for selective functionalization of isoprene, but also provides a guide to manipulate the regioselectivity for the N-functionalization of indazoles.
BICYCLIC DIHYDROPYRIMIDINE-CARBOXAMIDE DERIVATIVES AS RHO- KINASE INHIBITORS
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Paragraph 0419-0422, (2018/07/04)
Bicyclic dihydropyrimidine-carboxamide compounds of formula I described herein inhibit Rho Kinase and may be useful in the treatment of many disorders associated with ROCK enzymes mechanisms, such as pulmonary diseases including asthma, chronic obstructiv
Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors
Waldschmidt, Helen V.,Bouley, Renee,Kirchhoff, Paul D.,Lee, Pil,Tesmer, John J.G.,Larsen, Scott D.
supporting information, p. 1507 - 1515 (2018/04/09)
G protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2–Gβγ·GSK180736A and GRK5·CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity. From this campaign, we successfully generated two new potent GRK5 inhibitors, although neither exhibited selectivity over GRK2.
Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors
Waldschmidt, Helen V.,Homan, Kristoff T.,Cruz-Rodríguez, Osvaldo,Cato, Marilyn C.,Waninger-Saroni, Jessica,Larimore, Kelly M.,Cannavo, Alessandro,Song, Jianliang,Cheung, Joseph Y.,Kirchhoff, Paul D.,Koch, Walter J.,Tesmer, John J. G.,Larsen, Scott D.
, p. 3793 - 3807 (2016/05/24)
G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.
Potent, selective and orally bioavailable dihydropyrimidine inhibitors of Rho kinase (ROCK1) as potential therapeutic agents for cardiovascular diseases
Sehon, Clark A.,Wang, Gren Z.,Viet, Andrew Q.,Goodman, Krista B.,Dowdell, Sarah E.,Elkins, Patricia A.,Semus, Simon F.,Evans, Christopher,Jolivette, Larry J.,Kirkpatrick, Robert B.,Dul, Edward,Khandekar, Sanjay S.,Yi, Tracey,Wright, Lois L.,Smith, Gary K.,Behm, David J.,Bentley, Ross,Doe, Christopher P.,Hu, Erding,Lee, Dennis
supporting information; experimental part, p. 6631 - 6634 (2009/10/09)
Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.
Development of dihydropyridone indazole amides as selective rho-kinase inhibitors
Goodman, Krista B.,Cui, Haifeng,Dowdell, Sarah E.,Gaitanopoulos, Dimitri E.,Ivy, Robert L.,Sehon, Clark A.,Stavenger, Robert A.,Wang, Gren Z.,Viet, Andrew Q.,Xu, Weiwei,Ye, Guosen,Semus, Simon F.,Evans, Christopher,Fries, Harvey E.,Jolivette, Larry J.,Kirkpatrick, Robert B.,Dul, Edward,Khandekar, Sanjay S.,Yi, Tracey,Jung, David K.,Wright, Lois L.,Smith, Gary K.,Behm, David J.,Bentley, Ross,Doe, Christopher P.,Hu, Erding,Lee, Dennis
, p. 6 - 9 (2007/10/03)
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailabi
NOVEL COMPOUNDS
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Page/Page column 31, (2008/06/13)
Novel inhibitors of Rho-kinases are disclosed.
