ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor.
Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED(50) of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis.
Harris
Richard R
RR
Abbott Laboratories, Department R4PM, Bldg. AP9A, Abbott Park, IL 60064, USA. richard.r.harris@abbott.com
Black
Lawrence
L
Surapaneni
Sekhar
S
Kolasa
Teodozyj
T
Majest
Sandra
S
Namovic
Marian T
MT
Grayson
George
G
Komater
Victoria
V
Wilcox
Denise
D
King
Linda
L
Marsh
Kennan
K
Jarvis
Michael F
MF
Nuss
Merrill
M
Nellans
Hugh
H
Pruesser
Lee
L
Reinhart
Glenn A
GA
Cox
Bryan
B
Jacobson
Peer
P
Stewart
Andrew
A
Coghlan
Michael
M
Carter
George
G
Bell
Randy L
RL
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001792:Blood Platelets / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000503:physiopathology; D002351:Carrageenan; D002493:Central Nervous System Diseases / Q000139:chemically induced; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D015777:Eicosanoids / Q000097:blood; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins / Q000096:biosynthesis / Q000097:blood; D011724:Pyridazines / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013450:Sulfones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*
C495029:2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-(4-methanesulfonylphenyl)-2H-pyridazin-3-one; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D007375:Interleukin-1; D007527:Isoenzymes; D011453:Prostaglandins; D011724:Pyridazines; D011955:Receptors, Drug; D013450:Sulfones; D002351:Carrageenan; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases