Novel 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols with topical antiinflammatory activity.
The synthesis, biological evaluation, and structure-activity relationships of a series of 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols are described. These compounds show potent dose-dependent topical antiinflammatory activity in murine models of skin inflammation. This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin. These compounds were examined for their ability to inhibit the oxidative metabolism of arachidonic acid; they specifically inhibit the formation of prostacyclins in mouse macrophages. To study the effects of structure on the in vivo activity, three general features of the molecules were varied: the position of attachment of the pyridine nucleus (A), the second aromatic residue (B), and the nitrogen base on the ethanol chain (C). 1-[4-(4-Pyridyl)phenyl]-1-(4-fluorophenyl)-2- imidazolylethanol (2a, DuP 983) shows a very attractive profile of antiinflammatory activity and has been selected for clinical evaluation as a topical antiinflammatory agent.
Wright
S W
SW
Inflammatory Diseases Research, Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0353.
Harris
R R
RR
Collins
R J
RJ
Corbett
R L
RL
Green
A M
AM
Wadman
E A
EA
Batt
D G
DG
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D016718:Arachidonic Acid; D000001:Calcimycin; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003872:Dermatitis / Q000188:drug therapy / Q000209:etiology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate
C076199:1-(4-(4-pyridyl)phenyl)-1-(4-fluorophenyl)-2-imidazolylethanol; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D016718:Arachidonic Acid; D000001:Calcimycin; D010741:Phospholipases A; D013755:Tetradecanoylphorbol Acetate