Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models.
There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42--potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.
Department of Chemistry, Kalypsys Inc., 10420 Wateridge Circle, San Diego, CA 92121, USA.
Céline
C
Bonnefous
Joseph E
JE
Payne
Jeffrey
J
Roppe
Hui
H
Zhuang
Xiaohong
X
Chen
Kent T
KT
Symons
Phan M
PM
Nguyen
Marciano
M
Sablad
Natasha
N
Rozenkrants
Yan
Y
Zhang
Li
L
Wang
Daniel
D
Severance
John P
JP
Walsh
Nahid
N
Yazdani
Andrew K
AK
Shiau
Stewart A
SA
Noble
Peter
P
Rix
Tadimeti S
TS
Rao
Christian A
CA
Hassig
Nicholas D
ND
Smith
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D024841:Fluoroquinolones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005557:Formaldehyde / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D011719:Pyrazines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015363:Quinolones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C554421:4-((2-cyclobutyl-1H-imidazo(4,5-b)pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D008070:Lipopolysaccharides; D011719:Pyrazines; D015363:Quinolones; D005557:Formaldehyde; D052247:Nitric Oxide Synthase Type II