Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase.
Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.
Trejo
Alejandra
A
Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, R6-201, Palo Alto, California 94304, USA. alejandro.trejo@roche.com
Arzeno
Humberto
H
Browner
Michelle
M
Chanda
Sushmita
S
Cheng
Soan
S
Comer
Daniel D
DD
Dalrymple
Stacie A
SA
Dunten
Pete
P
Lafargue
JoAnn
J
Lovejoy
Brett
B
Freire-Moar
Jose
J
Lim
Julie
J
Mcintosh
Joel
J
Miller
Jennifer
J
Papp
Eva
E
Reuter
Deborah
D
Roberts
Rick
R
Sanpablo
Florentino
F
Saunders
John
J
Song
Kyung
K
Villasenor
Armando
A
Warren
Stephen D
SD
Welch
Mary
M
Weller
Paul
P
Whiteley
Phyllis E
PE
Zeng
Lu
L
Goldstein
David M
DM
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007275:Injections, Intravenous; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D020033:Protein Isoforms; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C478623:1-(4-(3-(4-fluorophenyl)-1H-pyrrolo(3,2-b)pyridin-2-yl)pyridin-2-ylamino)propan-2-ol; D004791:Enzyme Inhibitors; D007211:Indoles; D020033:Protein Isoforms; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases