RESUMO
The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.
Assuntos
Acetamidas/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Descoberta de Drogas , Inibidores de Lipoxigenase/farmacologia , Oxidiazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Conformação Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-AtividadeRESUMO
The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.
Assuntos
Oxidiazóis/farmacologia , Piperazinas/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Linfopenia/induzido quimicamente , Linfopenia/patologia , Estrutura Molecular , Oxidiazóis/administração & dosagem , Oxidiazóis/química , Piperazinas/administração & dosagem , Piperazinas/química , Ratos , Ratos Endogâmicos Lew , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-AtividadeRESUMO
Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
Assuntos
Descoberta de Drogas , Glucocorticoides/síntese química , Metanol/química , Receptores de Glucocorticoides/agonistas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artrite/tratamento farmacológico , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Concentração Inibidora 50 , Metanol/síntese química , Metanol/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Prednisolona/química , Prednisolona/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks.
Assuntos
Receptores de Glucocorticoides/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Triptaminas/química , Triptaminas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Sítios de Ligação , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Triptaminas/metabolismo , Triptaminas/uso terapêuticoRESUMO
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
Assuntos
Glucocorticoides/química , Glucocorticoides/farmacologia , Indóis/química , Indóis/farmacologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismo , Animais , Células HeLa , Humanos , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Piridinas/síntese química , Pirróis/síntese química , Receptores de Glucocorticoides/agonistas , Esteroides/química , Tecido Adiposo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Aromatase/biossíntese , Aromatase/genética , Inibidores da Aromatase/farmacologia , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Células Cultivadas , Indução Enzimática , Feminino , Humanos , Ligação de Hidrogênio , Insulina/sangue , Interleucina-1/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Piridinas/efeitos adversos , Piridinas/farmacologia , Pirróis/efeitos adversos , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Ativação TranscricionalRESUMO
A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.
Assuntos
Azepinas/química , Modelos Moleculares , Fenilpropionatos/química , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/química , Azepinas/síntese química , Sítios de Ligação , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/química , Cristalografia por Raios X , Fenilpropionatos/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Chemistry has been developed to specifically functionalize two structurally similar classes of indole-based MK2 inhibitors at positions prompted by a combination of X-ray crystallographic and computer assisted drug design. A gain in molecular potency was obtained by introducing aminomethyl groups to the lactam rings of 6-arylcarbamoyl-tetrahydro-beta-carbolinone and 6-arylcarbamoyl-dihydropyrazino[1,2-a]indolone MK2 inhibitors. In addition, improvements in molecular potency were achieved by expansion of the lactam from a 6- to 7-membered ring leading to 7-arylcarbamoyl-tetrahydro-[1,4]diazepino[1,2-a]indolones.