220378-41-6Relevant 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.
supporting information, p. 5096 - 5110 (2019/05/22)
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.
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
ω-(Imidazol-4-yl)alkane-1-sulfonamides: a new series of potent histamine H3 receptor antagonists
Tozer, Matthew J.,Buck, Ildiko M.,Cooke, Tracey,Kalindjian,Pether, Michael J.,Steel, Katherine I.M.
, p. 425 - 432 (2007/10/03)
ω-(1H-Imidazol-4-yl)alkane-1-sulfonamides were prepared and found to be potent histamine H3 receptor antagonists. High receptor affinity and a low difference in the data between the bioassays were achieved with 5-(1H-imidazol-4-yl)pentane-1-sulfonic acid 4-chlorobenzylamide (16). Good in vitro profiles were also obtained for 2-hydroxysulfonamide and vinylsulfonamide analogues. This complements and completes the existing set of imidazole-based sulfonamides and sulfamides. Copyright
1H-4(5)-substituted imidazole derivatives, their preparation and their use as histamine H3 receptor ligands
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, (2008/06/13)
A compound of the formula wherein R2is an optionally substituted Czto Cgalkylene or alkylene chain; R3is C2to C15optionally substituted hydrocarbyl; X is a bond or —NR4—, wherein
A new type of carboxypeptidase A inhibitors designed using an imidazole as a zinc coordinating ligand
Lee, Kyung Joo,Joo, Keum Chan,Kim, Eun-Jung,Lee, Mijoon,Kim, Dong H.
, p. 1989 - 1998 (2007/10/03)
2-(4-Imidazoyl)hydrocinnamic acid (1) and its congeners (2-4) having different length of alkyl chain spacers between the imidazole ring and the α-carbon to the carboxylate of 1 have been designed, synthesized and evaluated as inhibitors for carboxypeptidase A to show that they are competitive inhibitors for the enzyme. Inhibitor 1 was most potent having the K(i) value of 0.8 μM. The present study demonstrates that imidazole ring is an effective zinc coordinating ligand that can be useful for the design of inhibitors for zinc proteases.
