title: Discovery of a novel COX-2 inhibitor as an orally potent anti-pyretic and anti-inflammatory drug: design, synthesis, and structure-activity relationship.
abstract: Cyclooxygenase (COX) has been considered as a significant pharmacological target because of its pivotal roles in the prostaglandin biosynthesis and following cascades that lead to various (patho)physiological effects. Non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of fever, inflammation, and pain; however, nonselective COX inhibitors exhibit serious side-effects such as gastrointestinal damage because of their inhibitory activities against COX-1. Thus, COX-1 is constitutive and expressed ubiquitously and serves a housekeeping role, while COX-2 is inducible or upregulated by inflammatory/injury stimuli such as interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide in macrophage, monocyte, synovial, liver, and lung, and is associated with prostaglandin E₂ and prostacyclin production that evokes or sustains systemic/peripheral inflammatory symptoms. Also, hypersensitivity of aspirin is a significant concern clinically. Hence, design, synthesis, and structure-activity relationship of [2-{[(4-substituted)-pyridin-2-yl]carbonyl}-(6- or 5-substituted)-1H-indol-3-yl]acetic acid analogues were investigated to discover novel acid-type COX-2 inhibitor as an orally potent new-class anti-pyretic and anti-inflammatory drug. As significant findings, compounds 1-3 demonstrated potent COX-2 inhibitory activities with high selectivities for COX-2 over COX-1 in human cells or whole-blood in vitro, and demonstrated orally potent anti-pyretic activity against lipopolysaccharide-induced systemic-inflammatory fever model in F344 rats. Also compound 1 demonstrated orally potent anti-inflammatory activity against edema formation and a suppressive effect against PGE₂ production in carrageenan-induced peripheral-inflammation model on the paw of SD rats. These results suggest that compounds 1-3 are potential agents for the treatment of inflammatory disease and are useful for further pharmacological COX-2 inhibitor investigations.
authors: Nagoya Laboratories, Pfizer Global Research & Development, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. Shigeo_Hayashi@nifty.com
authors: Shigeo
authors: S
authors: Hayashi
authors: Yoko
authors: Y
authors: Sumi
authors: Naomi
authors: N
authors: Ueno
authors: Akio
authors: A
authors: Murase
authors: Junji
authors: J
authors: Takada
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058633:Antipyretics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004487:Edema / Q000188:drug therapy / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005334:Fever / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D058633:Antipyretics; D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D008070:Lipopolysaccharides; D011725:Pyridines; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone