ABSTRACT
The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Acetyl-CoA Carboxylase/chemistry , Lactams/chemistry , Lactams/chemical synthesis , Piperidines/chemistry , Piperidines/chemical synthesis , Pyrazoles/chemistry , Pyridones/chemistry , Pyridones/chemical synthesis , Alkylation , Cyclization , Molecular Structure , StereoisomerismABSTRACT
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
Subject(s)
Alzheimer Disease/drug therapy , Cyclin-Dependent Kinase 5/metabolism , Imidazoles/chemistry , Nerve Tissue Proteins/metabolism , Animals , Binding Sites , Caco-2 Cells , Crystallography, X-Ray , Cyclin E/antagonists & inhibitors , Cyclin E/metabolism , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Mice , Mice, Knockout , Nerve Tissue Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC(50)=ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.
Subject(s)
Alzheimer Disease/drug therapy , Amides/therapeutic use , Cyclin-Dependent Kinases/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Thiazoles/therapeutic use , Amides/chemical synthesis , CDC2-CDC28 Kinases/antagonists & inhibitors , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase 5 , Drug Evaluation, Preclinical , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesisABSTRACT
Two synthetic routes to a series of structurally novel kinase inhibitors containing a cis-1,3-disubstituted cyclobutane are described. The first route utilized addition of 3-aminocyclobutanol to 1,4-dinitroimidazole 5 as the crucial step in preparing 1, whereas the second route employed a novel 1,4-addition of 4-nitroimidazole 18 to in situ generated cyclobutenone 17 as the key reaction. This allowed for a stereoselective and shorter synthesis that eliminated the use of potentially explosive 1,4-dinitroimidazole 5. [structure: see text]
Subject(s)
Butanes/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Phosphotransferases/antagonists & inhibitors , Cyclization , Enzyme Inhibitors/pharmacology , Molecular Structure , Nitroimidazoles/chemistry , StereoisomerismABSTRACT
Reaction between ethyl 3-N,N-(dimethylamino)-2-isocyanoacrylate (1) and a primary amine (2) regioselectively affords 1-alkyl-4-imidazolecarboxylates (3) in good yields (52-89%). The method is applicable to unhindered and hindered amine substrates, as well as those containing reactive functionality such as alcohols and secondary and tertiary amines. [reaction: see text]
