266690-47-5Relevant 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.
Serine protease inhibitor
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Page/Page column 10, (2010/02/11)
A serine protease inhibitor having the formula (I), in which J is H, R1, R1—O—C(O)—, R1—C(O—, R1—SO2—, R3OOC—(CHR2)p—, (R2a,R2b)N—CO—(CHR2)p— or Het-CO—(CHR2)p—;W is an amino-acid of the formula —NH—CHR1—C(O)—, —NR4—CH((CH2)qC(O)OR1)—C(O)—, —NR4—CH((CH2)qC(O)N(R2a,R2b))—C(O)—, —NR4—CH((CH2)qC(O)Het)-C(O)—, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3 Piq, glutanyl or a (C1-C6) alkylester thereof;E is —NR2—CH2— or the fragment ?which is unsubstituted or substituted with (1-6C)alkyl, (1-6C)alkoxy or benzyloxy;R1 is selected form (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl, (3-12C)cycloalkyl and (3-12C)cycloalkyl(1-6C)alkylene, which groups are unsubstituted or substituted with (3-12C)cycloalkyl, (1-6C)alkoxy, oxo, OH, CF3 or halogen, and from (6-14C)aryl, (7-15C)aralkyl, (8-16C)aralkenyl and (14-20C)(bisary)alkyl, wherein the aryl groups are unsubstituted or substituted with (1-6C)alkyl, (3-12C)cycloalkyl, (1-6C)alkoxy, OH, CF3 or halogen;R2, R2a and R2b are each independently selected from H, (1-C)alkyl, (3-8C)alkenyl, (3-8C)alkynyl, (3-8C)cycloalkyl and (3-6C)cycloalkyl(1-4C)alkylene, which are unsubstituted or substituted with (3-6C)cycloalkyl, (1-6C)alkoxy, CF3 or halogen, and from (6-14C)aryl and (7-15C)aralkyl, wherein the aryl groups are unsubstituted or substituted with (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, CF3 or halogen;R3 is the same as R2 or is Het-(1-6C)alkyl;R4 is H or (1-3C)alkyl;X and Y are CH or N, with the proviso that they are not both N;Het is a 4-, 5- or 6-membered heterocycle containing one or more heteroatoms selected from O, N and S;m is 1 or 2;p is 1, 2 or 3;q is 1, 2 or 3;t is 2, 3 or 4;or a pharmaceutically acceptable addition salt or solvate thereof.
