131993-99-2Relevant 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 (2018)
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.
BENZOXAZOLE CARBOXAMIDE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)
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Page/Page column 83-84, (2009/08/16)
A compound having the structure set forth in Formula (I) or Formula (II): wherein the variables Y, R1, R2, R3, and R4 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.
3-Quinolinecarboxamides. A series of novel orally-active antiherpetic agents
Wentland,Perni,Dorff,Brundage,Castaldi,Bailey,Carabateas,Bacon,Young,Woods,Rosi,Drozd,Kullnig,Dutko
, p. 1580 - 1596 (2007/10/02)
A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7- positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency relative to acyclovir. In a single-dose mouse model of infection, one of the most potent derivatives in vitro, 1-(4- fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (97), displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple-dose regimen, however, 97 was 2-fold less potent. In mice dosed orally with 97, sustained plasma drug levels were evident that may account for the high efficacy observed. The molecular mechanism of action of these agents is not known; however, based on in vitro studies with acyclovir resistant mutants, it is likely that the mechanism differs from that of acyclovir. In vitro plaque-reduction potency was not generally predictive of oral efficacy in mice. An X-ray crystal structure of 97 corroborated the assignment of structure and provided useful insights as to the effect of conformation on plaque-reduction potency.
Quinolonecarboxamide compounds, their preparation and use as antivirals.
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, (2008/06/13)
Compounds of the formula STR1 where R is hydrogen, hydroxy, amino or lwer-alkyl; R1 is lower-alkyl, lower-alkenyl, cycloalkyl, pyridinyl, phenyl or substituted phenyl; R2 is hydrogen, amino or hydroxy; R6 is hydrogen or fluoro; and R7 is phenyl, pyridinyl or selected other heterocycles, have antiviral acitivity against herpes virus. The compounds are prepared from the corresponding carboxylic acids or ester, or by a tin-coupling reaction on the corresponding 7-halo compounds.
