Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.
Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.
Herberich
Brad
B
Department of Medicinal Chemistry, Amgen, Inc., Thousand Oaks, California 91320-1799, USA. brad.herberich@amgen.com
Cao
Guo-Qiang
GQ
Chakrabarti
Partha P
PP
Falsey
James R
JR
Pettus
Liping
L
Rzasa
Robert M
RM
Reed
Anthony B
AB
Reichelt
Andreas
A
Sham
Kelvin
K
Thaman
Maya
M
Wurz
Ryan P
RP
Xu
Shimin
S
Zhang
Dawei
D
Hsieh
Faye
F
Lee
Matthew R
MR
Syed
Rashid
R
Li
Vivian
V
Grosfeld
David
D
Plant
Matthew H
MH
Henkle
Bradley
B
Sherman
Lisa
L
Middleton
Scot
S
Wong
Lu Min
LM
Tasker
Andrew S
AS
D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C043388:phthalazine; C037219:quinoline; D048308:Mitogen-Activated Protein Kinase 14