Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationships.
A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.
Huang
H C
HC
Searle Research and Development, St. Louis, Missouri 63198, USA.
Li
J J
JJ
Garland
D J
DJ
Chamberlain
T S
TS
Reinhard
E J
EJ
Manning
R E
RE
Seibert
K
K
Koboldt
C M
CM
Gregory
S A
SA
Anderson
G D
GD
Veenhuizen
A W
AW
Zhang
Y
Y
Perkins
W E
WE
Burton
E G
EG
Cogburn
J N
JN
Isakson
P C
PC
Reitz
D B
DB
D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D002351:Carrageenan / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004487:Edema / Q000188:drug therapy; D006801:Humans; D007422:Intestines / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D016861:Cyclooxygenase Inhibitors; D013141:Spiro Compounds; D013449:Sulfonamides; D013450:Sulfones; C097781:4-(6-(3-chloro-4-methoxyphenyl)spiro(2.4)hept-5-en-5-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C097782:5-(3,5-dichloro-4-methoxyphenyl)-6-(4-(methylsulfonyl)phenyl)spiro(2.4)hept-5-ene