ABSTRACT
The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.
Subject(s)
Acrylamides/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/antagonists & inhibitors , Acrylamides/pharmacokinetics , Acrylamides/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/drug therapy , Dihydroorotate Dehydrogenase , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Female , Hypersensitivity, Delayed , Kinetics , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred DBA , Rats , Rats, Wistar , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxylic acid (3) was found to possess potent activity in the IgE-induced rat passive cutaneous anaphylaxis model which may be predictive of clinical antiallergic activity. Compared to disodium cromoglycate (DSCG, 1), 3 was less active following iv administration but unlike DSCG showed very significant oral activity. To explore the structural requirements for this activity, a range of tricyclic compounds was prepared and their activities were measured. Individual 2-carboxylic acids derived from imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles showed iv activities up to 10(3) times as potent as DSCG and many of them showed significant oral activity. From these, imidazo[1,2-a]quinoxaline-2-carboxylic acid 114 has been chosen for further development.
Subject(s)
Histamine H1 Antagonists/chemical synthesis , Hypersensitivity/drug therapy , Imidazoles/chemical synthesis , Pyrroles/chemical synthesis , Animals , Carboxylic Acids/chemical synthesis , Cromolyn Sodium/pharmacology , Histamine H1 Antagonists/pharmacology , Oxazines/chemical synthesis , Passive Cutaneous Anaphylaxis/drug effects , Quinoxalines/chemical synthesis , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesisABSTRACT
The synthesis and CNS activity of a noval class of annelated 1,4-benzodiazepines, the aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepines, are described. An investigation of the structure--activity relationships in the series derived from 8-chloro-2,4-dihydro-2-dimethylaminomethylene-6-phenyl-1H-imidazo[1,2-a][1,4]-benzodiazepin-1-one (10) led to the synthesis of a group of compounds with potent minor tranquillizer activity.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Benzodiazepinones/chemical synthesis , Aggression/drug effects , Animals , Anti-Anxiety Agents/toxicity , Anticonvulsants/chemical synthesis , Benzodiazepinones/pharmacology , Benzodiazepinones/toxicity , Chlorprothixene/pharmacology , Drug Synergism , Electroshock , Hexobarbital/pharmacology , Humans , Male , Mice , Motor Activity/drug effects , Pentylenetetrazole/antagonists & inhibitors , Strychnine/antagonists & inhibitorsABSTRACT
A number of derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone bearing new substituents on the 2-methyl group have been synthesized. It was established that most substitutions at this position reduce or remove the CNS depressant activity of methaqualone. From the series prepared only the 2-fluoromethyl derivative or certain isothiouronium salts, which could be hydrolyzed in vivo to the 2-mercaptomethyl derivative, showed activity of the same magnitude as methaqualone.
