ABSTRACT
Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemical synthesis , Pyrroles/chemical synthesis , 3-Phosphoinositide-Dependent Protein Kinases , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Ethylamines/chemical synthesis , Ethylamines/chemistry , Ethylamines/pharmacology , Humans , Models, Molecular , Phosphorylation , Protein Conformation , Proto-Oncogene Proteins c-akt/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Signal Transduction , Structure-Activity RelationshipABSTRACT
The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.