67698-61-7Relevant articles and documents
Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure-Based Drug Design
Hobson, Adrian D.,Judge, Russell A.,Aguirre, Ana L.,Brown, Brian S.,Cui, Yifang,Ding, Ping,Dominguez, Eric,Digiammarino, Enrico,Egan, David A.,Freiberg, Gail M.,Gopalakrishnan, Sujatha M.,Harris, Christopher M.,Honore, Marie P.,Kage, Karen L.,Kapecki, Nicolas J.,Ling, Christopher,Ma, Junli,Mack, Helmut,Mamo, Mulugeta,Maurus, Stefan,McRae, Bradford,Moore, Nigel S.,Mueller, Bernhard K.,Mueller, Reinhold,Namovic, Marian T.,Patel, Kaushal,Pratt, Steve D.,Putman, C. Brent,Queeney, Kara L.,Sarris, Kathy K.,Schaffter, Lisa M.,Stoll, Vincent,Vasudevan, Anil,Wang, Lei,Wang, Lu,Wirthl, William,Yach, Kimberly
, p. 11074 - 11100 (2019/01/04)
A HTS campaign identified compound 1, an excellent hit-like molecule to initiate medicinal chemistry efforts to optimize a dual ROCK1 and ROCK2 inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with pyrimidine afforded compounds with a clean CYP inhibition profile. Cocrystal structures of an early lead compound were obtained in PKA, ROCK1, and ROCK2. This provided critical structural information for medicinal chemistry to drive compound design. The structural data indicated the preferred configuration at the central benzylic carbon would be (R), and application of this information to compound design resulted in compound 16. This compound was shown to be a potent and selective dual ROCK inhibitor in both enzyme and cell assays and efficacious in the retinal nerve fiber layer model after oral dosing. This tool compound has been made available through the AbbVie Compound Toolbox. Finally, the cocrystal structures also identified that aspartic acid residues 176 and 218 in ROCK2, which are glutamic acids in PKA, could be targeted as residues to drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine group to the compound series resulted in compound 58, a potent and selective dual ROCK inhibitor with excellent predicted drug-like properties.
A practical in situ generation of the schwartz reagent. reduction of tertiary amides to aldehydes and hydrozirconation
Zhao, Yigang,Snieckus, Victor
, p. 390 - 393 (2014/04/03)
A new, highly efficient in situ protocol (Cp2ZrCl2/LiAlH(OBu-t)3) is described for the generation of the Schwartz reagent which provides a convenient method for the amide to aldehyde reduction and the regioselective hydrozirconation-iodination of alkynes and alkenes. Highlighted are chemoselective reductions of benzamides derived by directed ortho metalation (DoM) chemistry, allowing the synthesis of valuable 1,2,3-substituted benzaldehydes. The single-step, three-component process proceeds in a very short reaction time, shows excellent functional group compatibility, and uses inexpensive and long-storage stable reducing reagents.
PHENYLALKYLCARBOXYLIC ACID DELIVERY AGENTS
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Page/Page column 36, (2008/12/07)
The present invention provides phenylalkylcarboxylic acid compounds and compositions containing such compounds which facilitate the delivery of biologically active agents.
