Novel tricyclic inhibitors of IkappaB kinase.
The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
Kempson
James
J
Departments of Discovery Chemistry, Discovery Biology, and Metabolism and Pharmacokinetics and Synthesis and Analysis Technology Team, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543-4000, USA.
Spergel
Steven H
SH
Guo
Junqing
J
Quesnelle
Claude
C
Gill
Patrice
P
Belanger
Dominique
D
Dyckman
Alaric J
AJ
Li
Tianle
T
Watterson
Scott H
SH
Langevine
Charles M
CM
Das
Jagabandhu
J
Moquin
Robert V
RV
Furch
Joseph A
JA
Marinier
Anne
A
Dodier
Marco
M
Martel
Alain
A
Nirschl
David
D
Van Kirk
Katy
K
Burke
James R
JR
Pattoli
Mark A
MA
Gillooly
Kathleen
K
McIntyre
Kim W
KW
Chen
Laishun
L
Yang
Zheng
Z
Marathe
Punit H
PH
Wang-Iverson
David
D
Dodd
John H
JH
McKinnon
Murray
M
Barrish
Joel C
JC
Pitts
William J
WJ
D000818:Animals; D018360:Crystallography, X-Ray; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D008070:Lipopolysaccharides; D010080:Oxazoles; D011993:Recombinant Fusion Proteins; C439524:TNF protein, human; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D005982:Glutathione Transferase; D051550:I-kappa B Kinase