Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors.
The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.
Lin
Shuqun
S
Department of Immunology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Wrobleski
Stephen T
ST
Hynes
John
J
Pitt
Sidney
S
Zhang
Rosemary
R
Fan
Yi
Y
Doweyko
Arthur M
AM
Kish
Kevin F
KF
Sack
John S
JS
Malley
Mary F
MF
Kiefer
Susan E
SE
Newitt
John A
JA
McKinnon
Murray
M
Trzaskos
James
J
Barrish
Joel C
JC
Dodd
John H
JH
Schieven
Gary L
GL
Leftheris
Katerina
K
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D013455:Sulfur; D048308:Mitogen-Activated Protein Kinase 14; D009584:Nitrogen