The Discovery of Orally Active Triaminotriazine Aniline Amides as Inhibitors of p38 MAP Kinase

• Published in: Journal of medicinal chemistry 2004-12, Vol.47 (25), p.6283-6291
• Main Authors: Leftheris, Katerina, Ahmed, Gulzar, Chan, Ran, Dyckman, Alaric J, Hussain, Zahid, Ho, Kan, Hynes, John, Letourneau, Jeffrey, Li, Wei, Lin, Shuqun, Metzger, Axel, Moriarty, Kevin J, Riviello, Chris, Shimshock, Yvonne, Wen, James, Wityak, John, Wrobleski, Stephen T, Wu, Hong, Wu, Junjun, Desai, Madhuri, Gillooly, Kathleen M, Lin, Tsung H, Loo, Derek, McIntyre, Kim W, Pitt, Sidney, Shen, Ding Ren, Shuster, David J, Zhang, Rosemary, Diller, David, Doweyko, Arthur, Sack, John, Baldwin, Jack, Barrish, Joel, Dodd, John, Henderson, Ian, Kanner, Steve, Schieven, Gary L, Webb, Maria
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthritis, Experimental - drug therapy; Arthritis, Experimental - pathology; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Crystallography, X-Ray; Female; Humans; In Vitro Techniques; Medical sciences; Mice; Mice, Inbred BALB C; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Models, Molecular; Molecular Structure; Monocytes - drug effects; Monocytes - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - chemistry; Pharmacology. Drug treatments; Rats; Rats, Inbred Lew; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049521d

A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38α protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.