Subject(s)
Foreign-Body Migration/surgery , Hematoma, Epidural, Spinal/etiology , Spinal Cord Stimulation/instrumentation , Back Injuries/surgery , Back Injuries/therapy , Electrodes, Implanted/adverse effects , Foreign-Body Migration/diagnosis , Humans , Intervertebral Disc Displacement/surgery , Intervertebral Disc Displacement/therapy , Magnetic Resonance Imaging , Male , Middle Aged , Pain Management , Spinal Cord Stimulation/adverse effectsSubject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Dicarboxylic Acids/pharmacology , Glycine/analogs & derivatives , Phospholipases A/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Binding Sites , Dicarboxylic Acids/chemistry , Glycine/chemistry , Glycine/pharmacology , Humans , Models, Molecular , Molecular Structure , Phospholipases A/chemistryABSTRACT
A series of compounds in which the 4-acetyl-3-hydroxy-2-propylphenoxy moiety of the standard SRS-A antagonist, FPL-55712, is linked by a polymethylene or a polyether chain to substituted (aryloxy)alkanoic acids was prepared. The compounds were evaluated for their ability to antagonize SRS-A-induced contractions of guinea pig ilea and LTE-induced bronchoconstriction in the guinea pig. The results showed that the compounds were all less potent than FPL-55712 in vitro, yet surprisingly, most were more potent by the inhalation route of administration. Some of the most potent analogues were selected for further pharmacological evaluation and, by inhalation, exhibited selective antagonism of leukotrienes as compared with PAF or histamine. In comparison to FPL-55712, compounds 28 and 37 were more potent against LTE (40- and 80-fold, respectively), LTD (4- and 3-fold, respectively), and LTC (27- and 20-fold, respectively) induced bronchoconstriction when tested by inhalation.
Subject(s)
Fatty Acids/chemical synthesis , Muscle Contraction/drug effects , Phenyl Ethers/chemical synthesis , SRS-A/antagonists & inhibitors , Animals , Bronchi/drug effects , Bronchi/physiology , Fatty Acids/pharmacology , Guinea Pigs , In Vitro Techniques , Indicators and Reagents , Leukotriene E4 , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Phenyl Ethers/pharmacology , SRS-A/analogs & derivatives , SRS-A/pharmacology , Spectrophotometry , Structure-Activity RelationshipABSTRACT
(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo in a chemically induced mouse papilloma test; the toxicities were assessed in an in vivo mouse hypervitaminosis A test. Antipapilloma activity greater than the parent nonfluorinated ester was found for 1c (ethyl 12-fluororetinoate) and 23 and 39 (aromatic 4- and 6-fluororetinoid esters, respectively). A similar increase in antipapilloma activity was observed for 71 and 72, the aromatic 4- and 6-fluororetinoic acids, respectively, relative to 2 and for 73 (aromatic 4-fluororetinoid amide) relative to 4.
Subject(s)
Tretinoin/analogs & derivatives , Animals , Mice , Neoplasms, Experimental/drug therapy , Papilloma/drug therapy , Skin Neoplasms/drug therapy , Structure-Activity Relationship , Tretinoin/chemical synthesis , Tretinoin/therapeutic use , Tretinoin/toxicityABSTRACT
The syntheses of the ring and four side-chain dihydroretinoic acids and/or their esters, 3-7, are described. The syntheses of several other retinoids containing a substituted aromatic ring are also included. The biological activity of the compounds was evaluated in vivo in a chemically induced mouse skin papilloma test and in vitro in two vitamin A deficient assays. The activity observed for 1a, 1c, and 2a in the former test was partially retained in the dihydro derivatives 4b, 4c, and 6b. Similar results were found in the in vitro assays.
