Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-II).
Therapeutic interventions with Rho kinase (ROCK) inhibitors may effectively treat several disorders such as hypertension, stroke, cancer, and glaucoma. Herein we disclose the optimization and biological evaluation of potent novel ROCK inhibitors based on substituted indole and 7-azaindole core scaffolds. Substitutions on the indole C3 position and on the indole NH and/or amide NH positions all yielded potent and selective ROCK inhibitors (25, 42, and 50). Improvement of aqueous solubility and tailoring of in vitro and in vivo DMPK properties could be achieved through these substitutions.
Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA.
E Hampton
EH
Sessions
Sarwat
S
Chowdhury
Yan
Y
Yin
Jennifer R
JR
Pocas
Wayne
W
Grant
Thomas
T
Schröter
Li
L
Lin
Claudia
C
Ruiz
Michael D
MD
Cameron
Philip
P
LoGrasso
Thomas D
TD
Bannister
Yangbo
Y
Feng
D000818:Animals; D001665:Binding Sites; D065607:Cytochrome P-450 Enzyme Inhibitors; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D012995:Solubility; D014867:Water / Q000737:chemistry*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
C023422:7-azaindole dimer; D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D014867:Water; D054460:rho-Associated Kinases