Structure-activity relationships of the p38alpha MAP kinase inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796).
We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH(2) interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degrees C translating into K(d) values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.
Regan
John
J
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Research and Development Center, 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. jregan@rdg.boehringer-ingelheim.com
Capolino
Alison
A
Cirillo
Pier F
PF
Gilmore
Thomas
T
Graham
Anne G
AG
Hickey
Eugene
E
Kroe
Rachel R
RR
Madwed
Jeffrey
J
Moriak
Monica
M
Nelson
Richard
R
Pargellis
Christopher A
CA
Swinamer
Alan
A
Torcellini
Carol
C
Tsang
Michele
M
Moss
Neil
N
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D006361:Heating; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011489:Protein Denaturation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D010671:Phenylurea Compounds
D004791:Enzyme Inhibitors; D008024:Ligands; D008070:Lipopolysaccharides; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases; D009281:Naphthalenes; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; C452139:doramapimod; D010671:Phenylurea Compounds