Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase.
Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.
Liverton
N J
NJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Butcher
J W
JW
Claiborne
C F
CF
Claremon
D A
DA
Libby
B E
BE
Nguyen
K T
KT
Pitzenberger
S M
SM
Selnick
H G
HG
Smith
G R
GR
Tebben
A
A
Vacca
J P
JP
Varga
S L
SL
Agarwal
L
L
Dancheck
K
K
Forsyth
A J
AJ
Fletcher
D S
DS
Frantz
B
B
Hanlon
W A
WA
Harper
C F
CF
Hofsess
S J
SJ
Kostura
M
M
Lin
J
J
Luell
S
S
O'Neill
E A
EA
O'Keefe
S J
SJ
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D051381:Rats; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
C119801:5-(2-(1-phenylethylamino)pyridin-4-yl)-1-methyl-4-(3-(trifluoromethyl)phenyl)-2-(4-piperidinyl)imidazole; D000631:Aminopyridines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases