Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma.
The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocular pressure to baseline levels. The compounds also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and associated glaucoma.
Harrison
Bryce A
BA
Department of Medicinal Chemistry, Lexicon Pharmaceuticals, Princeton, New Jersey 08540, USA. bharrison@lexpharma.com
Whitlock
N Andrew
NA
Voronkov
Michael V
MV
Almstead
Zheng Y
ZY
Gu
Kun-jian
KJ
Mabon
Ross
R
Gardyan
Michael
M
Hamman
Brian D
BD
Allen
Jason
J
Gopinathan
Suma
S
McKnight
Beth
B
Crist
Mike
M
Zhang
Yulian
Y
Liu
Ying
Y
Courtney
Lawrence F
LF
Key
Billie
B
Zhou
Julia
J
Patel
Nita
N
Yates
Phil W
PW
Liu
Qingyun
Q
Wilson
Alan G E
AG
Kimball
S David
SD
Crosson
Craig E
CE
Rice
Dennis S
DS
Rawlins
David B
DB
D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005901:Glaucoma / Q000188:drug therapy / Q000503:physiopathology; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects; D054461:Lim Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009798:Ocular Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000959:Antihypertensive Agents; D006146:Guanidines; D009570:Nitriles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D014508:Urea; D054461:Lim Kinases; C095325:Limk2 protein, mouse