The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase.
Journal of medicinal chemistry 2004 Dec 2; 47(25):6283-91
Leftheris K K, Ahmed G G, Chan R R, Dyckman A AJ, Hussain Z Z, Ho K K, Hynes J J, Letourneau J J, Li W W, Lin S S, Metzger A A, Moriarty K KJ, Riviello C C, Shimshock Y Y, Wen J J, Wityak J J, Wrobleski S ST, Wu H H, Wu J J, Desai M M, Gillooly K KM, Lin T TH, Loo D D, McIntyre K KW, Pitt S S, Shen D DR, Shuster D DJ, Zhang R R, Diller D D, Doweyko A A, Sack J J, Baldwin J J, Barrish J J, Dodd J J, Henderson I I, Kanner S S, Schieven G GL
Departments of Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543-4000, USA. katerina.leftheris@bms.com
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 p38 alpha 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.