N-(3-(phenylcarbamoyl)arylpyrimidine)-5-carboxamides as potent and selective inhibitors of Lck: structure, synthesis and SAR.
N-3-(Phenylcarbamoyl)arylpyrimidine-5-carboxamides are a novel class of selective Lck inhibitors. This series of compounds derives its selectivity from a hydrogen bond with the gatekeeper Thr316 of the enzyme. X-ray co-crystal structural data, structure-activity relationships, and the synthesis of these inhibitors are reported herein.
Deak
Holly L
HL
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. holly.deak@amgen.com
Newcomb
John R
JR
Nunes
Joseph J
JJ
Boucher
Christina
C
Cheng
Alan C
AC
DiMauro
Erin F
EF
Epstein
Linda F
LF
Gallant
Paul
P
Hodous
Brian L
BL
Huang
Xin
X
Lee
Josie H
JH
Patel
Vinod F
VF
Schneider
Stephen
S
Turci
Susan M
SM
Zhu
Xiaotian
X
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013912:Threonine / Q000737:chemistry
D000577:Amides; D011743:Pyrimidines; D013912:Threonine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)