Potent, selective and orally bioavailable dihydropyrimidine inhibitors of Rho kinase (ROCK1) as potential therapeutic agents for cardiovascular diseases.
Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.
Sehon
Clark A
CA
Departments of Medicinal Chemistry, Investigative Biology, Vascular Biology, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. clark.a.sehon@gsk.com
Wang
Gren Z
GZ
Viet
Andrew Q
AQ
Goodman
Krista B
KB
Dowdell
Sarah E
SE
Elkins
Patricia A
PA
Semus
Simon F
SF
Evans
Christopher
C
Jolivette
Larry J
LJ
Kirkpatrick
Robert B
RB
Dul
Edward
E
Khandekar
Sanjay S
SS
Yi
Tracey
T
Wright
Lois L
LL
Smith
Gary K
GK
Behm
David J
DJ
Bentley
Ross
R
Doe
Christopher P
CP
Hu
Erding
E
Lee
Dennis
D
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000284:Administration, Oral; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology*; D018360:Crystallography, X-Ray; D007191:Indazoles / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000447:Aldehydes; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D054460:rho-Associated Kinases; C030986:pyrimidine