The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase.
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.
Leftheris
Katerina
K
Departments of Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543-4000, USA. katerina.leftheris@bms.com
Ahmed
Gulzar
G
Chan
Ran
R
Dyckman
Alaric J
AJ
Hussain
Zahid
Z
Ho
Kan
K
Hynes
John
J
Letourneau
Jeffrey
J
Li
Wei
W
Lin
Shuqun
S
Metzger
Axel
A
Moriarty
Kevin J
KJ
Riviello
Chris
C
Shimshock
Yvonne
Y
Wen
James
J
Wityak
John
J
Wrobleski
Stephen T
ST
Wu
Hong
H
Wu
Junjun
J
Desai
Madhuri
M
Gillooly
Kathleen M
KM
Lin
Tsung H
TH
Loo
Derek
D
McIntyre
Kim W
KW
Pitt
Sidney
S
Shen
Ding Ren
DR
Shuster
David J
DJ
Zhang
Rosemary
R
Diller
David
D
Doweyko
Arthur
A
Sack
John
J
Baldwin
Jack
J
Barrish
Joel
J
Dodd
John
J
Henderson
Ian
I
Kanner
Steve
S
Schieven
Gary L
GL
Webb
Maria
M
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
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