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Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Apr 24; Vol. 57 (8), pp. 3484-93. Date of Electronic Publication: 2014 Apr 09. - Publication Year :
- 2014
-
Abstract
- Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.
- Subjects :
- Animals
Drug Discovery
Female
Intracellular Signaling Peptides and Proteins chemistry
Mice
Models, Molecular
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases chemistry
Pyrimidines pharmacology
Structure-Activity Relationship
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Protein Kinase Inhibitors chemical synthesis
Protein Serine-Threonine Kinases antagonists & inhibitors
Pyrimidines chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24673130
- Full Text :
- https://doi.org/10.1021/jm500155b