RESUMO
A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
Assuntos
Amidas/síntese química , Amidoidrolases/antagonistas & inibidores , Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Prolina/análogos & derivados , Prolina/síntese química , Infecções Respiratórias/tratamento farmacológico , Administração Oral , Amidas/farmacologia , Amidoidrolases/metabolismo , Animais , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/crescimento & desenvolvimento , Humanos , Injeções Intravenosas , Testes de Sensibilidade Microbiana , Modelos Moleculares , Prolina/farmacologia , Ratos , Infecções Respiratórias/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.
Assuntos
Amidas/síntese química , Hidrocarbonetos Bromados/síntese química , Pirazóis/síntese química , Amidas/química , Técnicas de Química Combinatória , Hidrocarbonetos Bromados/química , Estrutura Molecular , Pirazóis/química , EstereoisomerismoRESUMO
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
Assuntos
Antineoplásicos/síntese química , Indazóis/síntese química , Morfolinas/síntese química , Piperidinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Indazóis/química , Indazóis/farmacologia , Camundongos , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Transplante de Neoplasias , Fosforilação , Piperidinas/química , Piperidinas/farmacologia , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil , Estereoisomerismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.
Assuntos
Hormônio Paratireóideo/química , Fragmentos de Peptídeos/química , Adenilil Ciclases/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Humanos , Lactamas/química , Dados de Sequência Molecular , Hormônio Paratireóideo/genética , Hormônio Paratireóideo/farmacologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Conformação Proteica , Engenharia de Proteínas , Ratos , Receptores de Hormônios Paratireóideos/agonistas , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.
Assuntos
Glucagon/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Piridinas/química , Relação Estrutura-AtividadeRESUMO
The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.