ABSTRACT
A series of benzobisthiazoles were screened for antiinflammatory activity in the carrageenan paw edema and adjuvant arthritis tests. Compound 26, 2,6-bis(N,N-diethylamino)benzo[1,2-d:5,4-d']bisthiazole, was found to inhibit the swelling of the uninjected paw in the prophylactic adjuvant arthritis model with an ED50 of 2.3 mg/kg orally. As with most compounds of this series, 26 was inactive in acute model of inflammation, such as paw edema; like steroids, it showed activity in the granuloma pouch assay but did not inhibit cyclooxygenase, indicating a mode of action different from the classical nonsteroidal antiinflammatory drugs (NSAID's). At doses higher than those producing antiinflammatory activity, 26 had some immunoregulating properties.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Thiazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Edema/drug therapy , Hemolytic Plaque Technique , Male , Mice , Mice, Inbred AKR , Molecular Structure , Rats , Rats, Inbred Strains , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Novel drugs presently introduced in the market are largely not discovered by rational design or by random screening but, rather, are products of evolution of existing leads (analogue research). It is suggested that this will change in the near future. Progress in a number of scientific disciplines will make it likely that drug design, but also systematic screening, will contribute more and more to novel drug discovery.
Subject(s)
Chemistry, Pharmaceutical , Pharmacology/trends , HumansABSTRACT
A group of indolyl-benzimidazolone-piperidines is described and the structure-activity with reference to the passive cutaneous anaphylaxis (PCA) in rats is discussed. Compound 7b, 4-(indolyl-3)-1-(benzimidazolonyl-propyl)-piperidine, which has the highest potency in this test, was studied in more detail with regard to antihistaminic and secretory cell stabilization properties.
Subject(s)
Benzimidazoles/chemical synthesis , Histamine H1 Antagonists/chemical synthesis , Piperidines/chemical synthesis , Animals , Basophils/metabolism , Benzimidazoles/pharmacology , Guinea Pigs , Histamine Release/drug effects , Humans , In Vitro Techniques , Male , Mast Cells/drug effects , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Passive Cutaneous Anaphylaxis/drug effects , Peritoneal Cavity/cytology , Piperidines/pharmacology , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
The synthesis and properties of the title compounds 1 are described. Many of these compounds are potent inhibitors of the passive cutaneous anaphylaxis reaction of rats against egg albumin challenge. Structural variations include substitutions in the 2, 3, 4, 5, 7, and 12 position of the nucleus 1. A novel rearrangement from a compound of the related [3,4-f] series to this group is reported.
