123566-47-2Relevant academic research and scientific papers
INHIBITORS OF RECEPTOR INTERACTING PROTEIN KINASE I FOR THE TREATMENT OF DISEASE
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, (2021/03/13)
Disclosed herein are compounds which inhibit RIPK1, pharmaceutical compositions, and methods of treatment of RIPK1 -mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer.
A convergent kilogram-scale synthesis of the PPARα Agonist LY518674: Discovery of a novel acid-mediated triazolone synthesis
Braden, Timothy M.,Coffey, D. Scott,Doecke, Christopher W.,LeTourneau, Michael E.,Martinelli, Michael J.,Meyer, Christopher L.,Miller, Richard D.,Pawlak, Joseph M.,Pedersen, Steven W.,Schmid, Christopher R.,Shaw, Bruce W.,Staszak, Michael A.,Vicenzi, Jeffrey T.
, p. 431 - 440 (2012/12/31)
The first kilogram-scale synthesis of the PPARα agonist LY518674 (1) is described. The de novo convergent synthetic approach involved coupling of two rapidly assembled components, triazolone formation via a novel acid-promoted cyclization reaction, and final step saponification, delivering the compound in 32.5% overall yield via eight total steps with a six-step longest linear sequence. A regioselective alkylation on the dianion of 4-hydroxyphenylbutyric acid allowed the direct preparation of one of the convergent coupling partners, carboxylic acid 12, and an unusual solvent effect enabled the installation of a urea group on a protected hydrazine, permitting the regiospecific preparation of the other coupling partner, semicarbazide mesylate 17. Sulfonic acids were found to effect the desired triazolone ring formation, affording 25 from the coupled precursor acyl semicarbazide 23. Following saponification of 25 to 1, a wide solubility differential between ethyl acetate extracts of 1 and solutions of 1 in anhydrous ethyl acetate was harnessed in the final crystallization step to deliver the final compound in high yield and purity. The novel acid-mediated triazolone formation was further evaluated on a range of additional substrates, showing the new methodology to be largely complementary to existing base-mediated triazolone syntheses.
Some Benzyl-Substituted Imidazoles, Triazoles, Tetrazoles, Pyridinethiones, and Structural Relatives as Multisubstrate Inhibitors of Dopamine β-Hydroxylase. 4. Structure-Activity Relationships at the Copper Binding Site
Kruse, Lawrence I.,Kaiser, Carl,DeWolf, Walter E.,Finkelstein, Joseph A.,Frazee, James S.,et al.
, p. 781 - 789 (2007/10/02)
Structure-activity relationships (SAR) were determined for novel multisubstrate inhibitors of dopamine β-hydroxylase (DBH; EC 1.14.17.1) by examining the effects upon in vitro inhibitory potencies resulting from structural changes at the copper-binding region of inhibitor.Attempts were made to determine replacement groups for the thione sulfur atom of the prototypical inhibitor 1-(4-hydroxybenzyl)imidazole-2-thione described previously.The synthesis and evaluation of oxygen and nitrogen analogues of the soft thione group demonstrated the sulfur atom to be necessary for optimal activity.An additional series of imidazole-2-thione relatives was prepared in an effort to probe the relationship between the pKa of the ligand group and inhibitor potency.In vitro inhibitory potency was shown not to correlate with ligand pKa over a range of approximately 10 pKa units, and a rationale for this is advanced.Additional ligand modifications were prepared in order to explore bulk tolerance at the enzyme oxygen binding site and to determine the effects of substituting a six-membered ligand group for the five-membered imidazole-2-thione ligand.
Dopamine-beta-hydroxylase inhibitors
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, (2008/06/13)
Compounds of Formula : in which n is 0 to 5, R is hydrogen or C1-4alkyl and X is hydrogen, halo, C1-4alkyl, CN, NO2, SO2NH2, COOH, CHO, OH, CH2OH, C1-4alkoxy, CF3, SO
