title: The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase.
abstract: 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.
authors.affiliation: Departments of Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543-4000, USA. katerina.leftheris@bms.com
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
authors.forename: Gulzar
authors.initials: G
authors.lastname: Ahmed
authors.forename: Ran
authors.initials: R
authors.lastname: Chan
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
authors.forename: Zahid
authors.initials: Z
authors.lastname: Hussain
authors.forename: Kan
authors.initials: K
authors.lastname: Ho
authors.forename: John
authors.initials: J
authors.lastname: Hynes
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Letourneau
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Shuqun
authors.initials: S
authors.lastname: Lin
authors.forename: Axel
authors.initials: A
authors.lastname: Metzger
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Moriarty
authors.forename: Chris
authors.initials: C
authors.lastname: Riviello
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Shimshock
authors.forename: James
authors.initials: J
authors.lastname: Wen
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Wrobleski
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Junjun
authors.initials: J
authors.lastname: Wu
authors.forename: Madhuri
authors.initials: M
authors.lastname: Desai
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillooly
authors.forename: Tsung H
authors.initials: TH
authors.lastname: Lin
authors.forename: Derek
authors.initials: D
authors.lastname: Loo
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitt
authors.forename: Ding Ren
authors.initials: DR
authors.lastname: Shen
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: Rosemary
authors.initials: R
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Diller
authors.forename: Arthur
authors.initials: A
authors.lastname: Doweyko
authors.forename: John
authors.initials: J
authors.lastname: Sack
authors.forename: Jack
authors.initials: J
authors.lastname: Baldwin
authors.forename: Joel
authors.initials: J
authors.lastname: Barrish
authors.forename: John
authors.initials: J
authors.lastname: Dodd
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.forename: Steve
authors.initials: S
authors.lastname: Kanner
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.forename: Maria
authors.initials: M
authors.lastname: Webb
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000577:Amides; D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; C494721:N-methoxy-4-methyl-3-(4-(methyl(neopentyl)amino)-6-(4-methyl-1,4-diazepan-1-yl)-1,3,5-triazin-2-ylamino)benzamide; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases