215453-25-1Relevant articles and documents
Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors
Ray, Peter,Wright, Jane,Adam, Julia,Bennett, Johnathan,Boucharens, Sylviane,Black, Darcey,Cook, Andrew,Brown, Angus R.,Epemolu, Ola,Fletcher, Dan,Haunso, Anders,Huggett, Margaret,Jones, Phil,Laats, Steven,Lyons, Amanda,Mestres, Jordi,De Man, Jos,Morphy, Richard,Rankovic, Zoran,Sherborne, Brad,Sherry, Lorcan,Van Straten, Nicole,Westwood, Paul,Zaman, Guido Z.R.
supporting information; scheme or table, p. 97 - 101 (2011/02/28)
Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
1-Aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors
Rewinkel,Lucas,Van Galen,Noach,Van Dinther,Rood,Jenneboer,Van Boeckel
, p. 685 - 690 (2007/10/03)
Replacement of the highly basic benzamidine moiety of NAPAP by the moderately basic 1-aminoisoquinoline moiety resulted in thrombin inhibitors with improved selectivity towards trypsin and enhanced Caco-2 cell permeability.
