Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.
Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.
Discovery Research, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, UK. p.ray@btinternet.com
Peter
P
Ray
Jane
J
Wright
Julia
J
Adam
Sylviane
S
Boucharens
Darcey
D
Black
Angus R
AR
Brown
Ola
O
Epemolu
Dan
D
Fletcher
Margaret
M
Huggett
Phil
P
Jones
Steven
S
Laats
Amanda
A
Lyons
Jos
J
de Man
Richard
R
Morphy
Brad
B
Sherborne
Lorcan
L
Sherry
Nicole van
Nv
Straten
Paul
P
Westwood
Mark
M
York
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy; D007546:Isoquinolines / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000588:Amines; D007546:Isoquinolines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C039109:isoquinoline; C049347:fasudil