ABSTRACT
Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
Subject(s)
IMP Dehydrogenase/antagonists & inhibitors , Mycophenolic Acid/analogs & derivatives , Animals , Cell Division/drug effects , Female , Hemolytic Plaque Technique , Humans , Lymphocytes/cytology , Lymphocytes/drug effects , Mice , Mice, Inbred C3H , Mycophenolic Acid/pharmacology , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
The synthesis and antiallergic activity of a series of novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles are described. A number of the compounds inhibit the release of histamine from anti-IgE stimulated basophils obtained from allergic donors. Optimal inhibition is exhibited in benzothiophenes with a 3-alkoxy substituent in combination with a 5-methoxy, 6-methoxy, or a 5,6-dimethoxy group. Compound 13c (CI-959) also inhibited respiratory burst of human neutrophils and the release of mediators from anti-IgE-stimulated human chopped lung.
Subject(s)
Benzofurans/chemical synthesis , Histamine Antagonists/chemical synthesis , Naphthalenes/chemical synthesis , Tetrazoles/chemical synthesis , Thiophenes/chemical synthesis , Antibodies, Anti-Idiotypic/immunology , Basophils/drug effects , Basophils/immunology , Basophils/physiology , Benzofurans/pharmacology , Eosinophils/drug effects , Eosinophils/physiology , Histamine Antagonists/pharmacology , Histamine Release/drug effects , Humans , Hypersensitivity/blood , Immunoglobulin E/immunology , Lung/drug effects , Lung/metabolism , Molecular Structure , Naphthalenes/pharmacology , Neutrophils/drug effects , Neutrophils/physiology , Respiratory Burst/drug effects , Structure-Activity Relationship , Tetrazoles/pharmacology , Thiophenes/pharmacologyABSTRACT
Reaction of 3-amino derivatives of the nematocides tetramisole and levamisole with variously substituted benzoylisocyanates gave a series of benzoylureas I which were tested for activity against helminths and ectoparasites. Compounds bearing 2,6-difluoro and 4-trifluoromethyl substituents had potent nematocidal activity in both mice and sheep. No antiectoparasitic activity was observed.
Subject(s)
Anthelmintics/chemical synthesis , Animals , Anthelmintics/therapeutic use , Chemical Phenomena , Chemistry , Female , Levamisole/analogs & derivatives , Male , Mice , Nematode Infections/drug therapy , Sheep , Structure-Activity Relationship , Tetramisole/analogs & derivativesABSTRACT
The synthesis and antiallergic potential of a series of novel indolecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated basophilic leukocytes obtained from allergic donors. Optimal inhibition is exhibited by compounds with 3-alkoxy, 5-methoxy, and 1-phenyl substituents on the indole core structure. Compound 8d (5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide; designated CI-949) is a potent inhibitor of histamine release from human basophils and from guinea pig and human chopped lung.
