ABSTRACT
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.
Subject(s)
Amides/chemical synthesis , Antirheumatic Agents/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Humans , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Rats , Structure-Activity Relationship , Time Factors , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
SAR studies led to the identification of 4-(3-benzoylamino-6-methyl-anilino)quinazolines as potent and selective inhibitors of p38 MAP kinase. Further optimisation led to the identification of a series of 4-(3-benzoylamino-6-methyl-anilino)pyrimidines as potent inhibitors of the p38 MAP kinase signalling pathway in vitro and in vivo.
Subject(s)
Aniline Compounds/chemical synthesis , Pyrimidines/chemical synthesis , Quinazolines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Administration, Oral , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antirheumatic Agents/chemical synthesis , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Binding Sites , Biological Availability , Crystallography, X-Ray , Humans , In Vitro Techniques , Models, Molecular , Protein Binding , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Signal Transduction , Structure-Activity Relationship , Time Factors , p38 Mitogen-Activated Protein Kinases/physiologyABSTRACT
The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.
