RESUMO
A series of indeno[1,2-c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. The synthesis, structure-activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed.
Assuntos
Descoberta de Drogas , Heme/metabolismo , Indenos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Indenos/síntese química , Indenos/química , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade , eIF-2 Quinase/metabolismoRESUMO
A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.
Assuntos
Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Receptor de Colecistocinina A/metabolismo , Receptor de Colecistocinina B/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A novel strategy for the synthesis of cholecystokinin-2 receptor ligands was developed. The route employs a solution-phase synthesis of a series of anthranilic sulfonamides followed by a resin capture purification strategy to produce multi-milligram quantities of compounds for bioassay. The synthesis was used to produce >100 compounds containing various functional groups, highlighting the general applicability of this strategy and to address specific metabolism issues in our CCK-2 program.
Assuntos
Colecistocinina/metabolismo , Técnicas de Química Combinatória , Receptor de Colecistocinina B/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Animais , Desenho de Fármacos , Humanos , Ligantes , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , ortoaminobenzoatos/químicaRESUMO
A series of iminodiacetic acid (IDA)-linked polyamides (DpPyPyPy-IDA-PyPyPyDp) were prepared and constitute polyamides joined head-to-head by a functionalizable five-atom linker. It was found that the IDA linker exerts a unique influence over the DNA binding conformation differing from both the beta-alanine (extended) or gamma-aminobutyric acid (hairpin) linkers, resulting in cooperative parallel side-by-side 2:1 binding in an extended conformation most likely with a staggered versus stacked alignment. A generalized variant of a fluorescent intercalator displacement (FID) assay conducted on a series of hairpin deoxyoligonucleotides containing a systematically varied A/T-rich binding-site size was used to distinguish between the binding modes of the IDA-linked polyamides.
Assuntos
DNA/química , Iminoácidos/química , Nylons/química , Sequência de Bases , DNA/metabolismo , Iminoácidos/síntese química , Iminoácidos/metabolismo , Cinética , Conformação de Ácido Nucleico , Nylons/síntese química , Nylons/metabolismoRESUMO
A series of saturated heterocyclic analogues of distamycin were prepared and examined. A fluorescent intercalator displacement (FID) assay conducted on p[dA]-p[dT] DNA to obtain C(50) values and a hairpin deoxyoligonucleotide containing an A/T-rich binding site was used to evaluate DNA binding affinity. It is observed that saturated heterocycles greatly reduce the DNA binding relative to distamycin.
Assuntos
DNA/metabolismo , Distamicinas/metabolismo , Distamicinas/síntese química , Distamicinas/químicaRESUMO
A series of alpha-substituted beta-alanine (beta) linked polyamides (DbaPyPyPy-beta*-PyPyPy) were prepared and examined. This resulted in the observation that while most substituents disrupt DNA binding, (R)-alpha-methoxy-beta-alanine (beta((R)-OMe)) maintains strong binding affinity and preferentially adopts a hairpin versus extended binding mode, providing an alternative hairpin linker to gamma-aminobutyric acid (gamma). A generalized variant of a fluorescent intercalator displacement assay conducted on a series of hairpin deoxyoligonucleotides containing a systematically varied A/T-rich binding site size was developed to distinguish between the extended binding of the parent beta-alanine 1 (DbaPyPyPy-beta-PyPyPy) and the hairpin binding of 3 (DbaPyPyPy-beta((R)-OMe)-PyPyPy).
