Evolution of the thienopyridine class of inhibitors of IkappaB kinase-beta: part I: hit-to-lead strategies.
High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IkappaB kinase-beta (IKKbeta), a key regulatory enzyme in the nuclear factor-kappaB (NF-kappaB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.
Morwick
Tina
T
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06801-0368, USA. tmorwick@rdg.boeringer-ingelheim.com
Berry
Angela
A
Brickwood
Janice
J
Cardozo
Mario
M
Catron
Katrina
K
DeTuri
Molly
M
Emeigh
Jonathan
J
Homon
Carol
C
Hrapchak
Matt
M
Jacober
Stephen
S
Jakes
Scott
S
Kaplita
Paul
P
Kelly
Terence A
TA
Ksiazek
John
J
Liuzzi
Michel
M
Magolda
Ronald
R
Mao
Can
C
Marshall
Daniel
D
McNeil
Daniel
D
Prokopowicz
Anthony
A
Sarko
Christopher
C
Scouten
Erika
E
Sledziona
Cynthia
C
Sun
Sanxing
S
Watrous
Jane
J
Wu
Jiang Ping
JP
Cywin
Charles L
CL