Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors

Allard Kaptein; Arthur Oubrie; Edwin de Zwart; Niels Hoogenboom; Joeri de Wit; Bas van de Kar; Maaike van Hoek; Gerard Vogel; Vera de Kimpe; Carsten Schultz-Fademrecht; Judith Borsboom; Mario van Zeeland; Judith Versteegh; Bert Kazemier; Jeroen de Roos; Frank Wijnands; John Dulos; Martin Jaeger; Paula Leandro-Garcia; Tjeerd Barf

doi:10.1016/j.bmcl.2011.04.016

Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3823-7. doi: 10.1016/j.bmcl.2011.04.016. Epub 2011 Apr 16.

Affiliation

¹ Merck Research Laboratories, MSD, Oss, The Netherlands.

PMID: 21565498
DOI: 10.1016/j.bmcl.2011.04.016

Abstract

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 pK(a) 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 (EC(50) 7.4 nM) and submicromolar cellular target engagement activity (EC(50) 0.5 μM).

MeSH terms

Administration, Oral
Animals
Binding, Competitive
Biological Availability
Caco-2 Cells
Chromatography, High Pressure Liquid
Crystallography, X-Ray
Disease Models, Animal
Drug Discovery*
Enzyme Activation / drug effects
Humans
Inhibitory Concentration 50
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / chemistry
Molecular Structure
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Rats
Spiro Compounds / chemical synthesis*
Spiro Compounds / chemistry
Spiro Compounds / pharmacology
Stereoisomerism
Structure-Activity Relationship
Substrate Specificity

Substances

Intracellular Signaling Peptides and Proteins
Piperidines
Protein Kinase Inhibitors
Spiro Compounds
MAP-kinase-activated kinase 2
Protein Serine-Threonine Kinases