- Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase
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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.
- 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.
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p. 5096 - 5110
(2019/05/22)
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- Pyrazoline derivatives for treating cerebrovascular diseases
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2-Pyrazoline derivatives of the formula (A): STR1 where R1 is a pyridyl, a pyrazyl or an alkoxy group; and R2 is a hydrogen atom, an alkyl, a pyridyl, a furyl, phenyl or a substituted phenyl group, and to a process for producing the same. Therapeutic agents for treating cerebrovascular diseases containing, as the active ingredient, a 2-pyrazoline derivative represented by the formula (G): STR2 where R3 is a hydrogen atom, an alkyl, acetyl, an alkoxycarbonyl, an amino, benzoyl, a substituted benzoyl, a pyridylcarbonyl, a furylcarbonyl, a thienylcarbonyl, a pyrazylcarbonyl, an N-substituted carbamoyl, an N-substituted thiocarbamoyl, or carboxy group; and R4 is a hydrogen atom, an alkyl, a pyridyl, a thienyl, a furyl, cyclohexyl, phenyl or a substituted phenyl group or a pharmaceutically acceptable salt thereof. These therapeutic agents cope with cerebral edemas in the acute stage of cerebral apoplexy and regulates the whole-body and intracranial body circulation, thereby protecting ischemic lesions and minimizing the spread to affected parts.
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