111157-50-7Relevant academic research and scientific papers
Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase
Harris, Philip A.,Faucher, Nicolas,George, Nicolas,Eidam, Patrick M.,King, Bryan W.,White, Gemma V.,Anderson, Niall A.,Bandyopadhyay, Deepak,Beal, Allison M.,Beneton, Veronique,Berger, Scott B.,Campobasso, Nino,Campos, Sebastien,Capriotti, Carol A.,Cox, Julie A.,Daugan, Alain,Donche, Frederic,Fouchet, Marie-Hélène,Finger, Joshua N.,Geddes, Brad,Gough, Peter J.,Grondin, Pascal,Hoffman, Bonnie L.,Hoffman, Sandra J.,Hutchinson, Susan E.,Jeong, Jae U.,Jigorel, Emilie,Lamoureux, Pauline,Leister, Lara K.,Lich, John D.,Mahajan, Mukesh K.,Meslamani, Jamel,Mosley, Julie E.,Nagilla, Rakesh,Nassau, Pamela M.,Ng, Sze-Ling,Ouellette, Michael T.,Pasikanti, Kishore K.,Potvain, Florent,Reilly, Michael A.,Rivera, Elizabeth J.,Sautet, Stéphane,Schaeffer, Michelle C.,Sehon, Clark A.,Sun, Helen,Thorpe, James H.,Totoritis, Rachel D.,Ward, Paris,Wellaway, Natalie,Wisnoski, David D.,Woolven, James M.,Bertin, John,Marquis, Robert W.
, p. 5096 - 5110 (2019)
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
ISOQUINOLINES AS INHIBITORS OF HPK1
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Paragraph 2346; 2347, (2018/10/21)
Isoquinoline compounds and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibitng HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the isoquinoline compounds.
Meta-substituted aryl(thio)ethers as potent partial agonists (or antagonists) for the histamine H3 receptor lacking a nitrogen atom in the side chain
Pelloux-Léon, Nadia,Fkyerat, Abdellatif,Piripitsi, Antonia,Tertiuk, Wasyl,Schunack, Walter,Stark, Holger,Garbarg, Monique,Ligneau, Xavier,Arrang, Jean-Michel,Schwartz, Jean-Charles,Ganellin, C. Robin
, p. 3264 - 3274 (2007/10/03)
4-(3-Aryloxypropyl)-1H-imidazoles, which possess a meta-positioned substituent in the aryl ring, have been synthesized and tested for activity at histamine H3 receptors. The compounds having a CN, Me, or Br substituent were found to be antagoni
Steric enhancement of imidazole basicity in cis-urocanic acid derivatives: Models for the action of chymotrypsin
Cloninger, Mary J.,Frey, Perry A.
, p. 323 - 333 (2007/10/03)
To test the hypothesis that substrate-induced steric compression between His 57 and Asp 102 at the active site of chymotrypsin can increase the basicity of His 57, we have synthesized the cis- and trans-isomers of 2- bromo-3-(N-tritylimidazole)-2-propenoic acid and 2-chloro-3(N- tritylimidazole)-2-propenoic acid and compared selected properties with those of cis- and trans-urocanic acids. The cis-isomers display low field 1H NMR signals at 17 ppm in dimethylsulfoxide, similar to cis-urocanic acid; whereas the trans-isomers do not show strong hydrogen bonds. Increasing the size of the C2 substituent (H Cl Br) in the cis-isomers increases the pK(a) of the imidazolium group from 6.78 for H to 7.81 and 9.10 for Cl and Br, respectively; whereas the pK(a)s of the trans isomers are all 6.0 ± 0.1. The results indicate that the cis-urocanic acid derivatives with large substituents at C2 act as proton sponges in water, and they support the concept that steric compression in the catalytic triad of chymotrypsin can increase the basicity of His 57.
SELECTIVE N-ALKYLATION OF (E)-UROCANIC ACID
Lauth- Viguerie, Nancy de,Sergueeva, Natalia,Damiot, Monique,Mawlawi, Hiba,Riviere, Monique,Lattes, Armand
, p. 1561 - 1578 (2007/10/02)
Various methods of selective alkylation of the N(τ)- and N(?)-nitrogen atoms of the (E)-urocanic acid derivatives are reported.Solid-liquid phase transfer catalysis gave the best results for N(τ)-alkylation of urocanic acid alkyl esters.Liquid-liquid phase transfer catalysis allowed direct N(τ)-akylation of urocanic acid itself.The N(?)-nitrogen atom was alkylated after protection of the N(τ)-nitrogen with a phenacyl group.
IMPROVED SYNTHESES OF VINYL IMIDAZOLES
Griffith, Robert K.,DiPietro, Richard A.
, p. 1761 - 1770 (2007/10/02)
A series of vinylimidazoles were synthesized via Witting reactions on N-tritylimidazole-4-carboxaldehyde.Activated phosphonate ylids afforded yields in excess of 90percent while the yields from unactivated ylids ranged from 10-82percent.The trityl group m
