948589-00-2Relevant articles and documents
Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors
Kaptein, Allard,Oubrie, Arthur,De Zwart, Edwin,Hoogenboom, Niels,De Wit, Joeri,Van De Kar, Bas,Van Hoek, Maaike,Vogel, Gerard,De Kimpe, Vera,Schultz-Fademrecht, Carsten,Borsboom, Judith,Van Zeeland, Mario,Versteegh, Judith,Kazemier, Bert,De Roos, Jeroen,Wijnands, Frank,Dulos, John,Jaeger, Martin,Leandro-Garcia, Paula,Barf, Tjeerd
scheme or table, p. 3823 - 3827 (2011/08/02)
The identification of a potent, selective, and orally available MK2 inhibitor series is described. The initial absence of oral bioavailability was successfully tackled by moving the basic nitrogen of the spiro-4-piperidyl moiety towards the electron-deficient pyrrolepyridinedione core, thereby reducing the pKa and improving Caco-2 permeability. The resulting racemic spiro-3-piperidyl analogues were separated by chiral preparative HPLC, and the activity towards MK2 inhibition was shown to reside mostly in the first eluting stereoisomer. This led to the identification of new MK2 inhibitors, such as (S)-23, with low nanomolar biochemical inhibition (EC50 7.4 nM) and submicromolar cellular target engagement activity (EC50 0.5 μM).
Design and synthesis of 3,3-piperidine hydroxamate analogs as selective TACE inhibitors
Lombart, Henry-Georges,Feyfant, Eric,Joseph-McCarthy, Diane,Huang, Adrian,Lovering, Frank,Sun, LinHong,Zhu, Yi,Zeng, Congmei,Zhang, Yuhua,Levin, Jeremy
, p. 4333 - 4337 (2008/02/11)
Structure-based methods were used to design β-sulfone 3,3-piperidine hydroxamates as TACE inhibitors with the aim of improving selectivity for TACE versus MMP-13. Several compounds in this series were synthesized and evaluated in enzymatic and cell-based
