1127307-68-9Relevant academic research and scientific papers
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.
4-(4-PYRIDINYL)-BENZAMIDES AND THEIR USE AS ROCK ACTIVITY MODULATORS
-
Page/Page column 184-185, (2009/04/25)
The present invention relates to novel 4-(4-pyridyl)-benzamides of the formula (I). The compounds I possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of Rho kinases (ROCKs). R1 and R2 are, independently of each other, hydrogen, hydroxy, cyano, C1-C8-alkyl, C1- C8-haloalkyl, C1-C8-alkoxy or C1-C8-haloalkoxy; R3, R4, R5 and R6 are, independently of each other, hydrogen, hydroxy, halogen, cyano, C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, C1-C8-haloalkoxy, amino, C1-C8-alkylamino or di-(C1-C8-alkyl)-amino; R7 is hydrogen, C1-C8-alkyl, C1-C8-haloalkyl, aryl or aryl-C1-C8-alkyl; R8 is a group of the formula -X-W, where X is a single bond, C1-C4-alkylene or C1-C4-alkylene-O-, where the alkylene group in the three last-mentioned radicals may be linear or branched and may be partly or fully halogenated and/or may be substituted by a hydroxyl group and/or may be interrupted by an oxygen atom; and W is a cyclic radical selected from phenyl and a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring which contains as ring members 1, 2 or 3 heteroatoms selected from O, S and N and optionally 1 or 2 carbonyl groups; R9 is a group of the formula -Y-Z, where Z is hydrogen, halogen, OR11, NR12R13, S(O)m-R14, phenyl which may carry 1, 2, 3 or 4 substituents R15 or a 5- or 6-membered saturated, partly unsaturated or aromatic heterocyclic ring; and Y is linear or branched C1C4-alkylene which may be partly or fully halogenated and/or may be substituted by a hydroxyl group and/or a phenyl ring; or, in case Z is phenyl or the 5- or 6-membered heterocyclic ring as defined above, Y can also be a single bond.
