RESUMO
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metaboliteâgenerated by aldehyde oxidase (AO)âpossessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.
Assuntos
Doenças Respiratórias , Canais de Potencial de Receptor Transitório , Humanos , Canais de Potencial de Receptor Transitório/metabolismo , Canal de Cátion TRPA1 , Aldeído Oxidase/metabolismo , Oxirredutases/metabolismo , Proteínas do Citoesqueleto/metabolismoRESUMO
Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1. Using a structure-based drug design approach, the kinase selectivity of the molecules was significantly improved by inducing and stabilizing an unusual P-loop folded binding mode. The metabolic liabilities of the initial 7-azaindole high-throughput screening hit were mitigated by addressing a key metabolic soft spot along with physicochemical property-based optimization. The resulting spiro-azaindoline HPK1 inhibitors demonstrated improved in vitro ADME properties and the ability to induce cytokine production in primary human T-cells.
RESUMO
Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
Assuntos
Asma/tratamento farmacológico , Inflamação Neurogênica/tratamento farmacológico , Dor/tratamento farmacológico , Prurido/tratamento farmacológico , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Canal de Cátion TRPA1/antagonistas & inibidores , Adolescente , Adulto , Animais , Estudos de Coortes , Modelos Animais de Doenças , Cães , Método Duplo-Cego , Feminino , Cobaias , Voluntários Saudáveis , Humanos , Isotiocianatos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Dor/induzido quimicamente , Prurido/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Canal de Cátion TRPA1/deficiência , Resultado do Tratamento , Adulto JovemRESUMO
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21 was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.
Assuntos
Asma/tratamento farmacológico , Furanos/uso terapêutico , Purinas/uso terapêutico , Canal de Cátion TRPA1/antagonistas & inibidores , Animais , Asma/induzido quimicamente , Asma/complicações , Células CHO , Cricetulus , Furanos/síntese química , Furanos/metabolismo , Cobaias , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Ligantes , Masculino , Estrutura Molecular , Ovalbumina , Oxidiazóis/síntese química , Oxidiazóis/metabolismo , Oxidiazóis/uso terapêutico , Ligação Proteica , Purinas/síntese química , Purinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Canal de Cátion TRPA1/metabolismoRESUMO
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat.
Assuntos
Barreira Hematoencefálica/metabolismo , Receptores Nucleares Órfãos/agonistas , Quinolinas/química , Sulfonas/química , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Humanos , Ligação de Hidrogênio , Receptores X do Fígado , Receptores Nucleares Órfãos/metabolismo , Ligação Proteica , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacocinéticaRESUMO
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/química , Hidantoínas/química , Imidazóis/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Hidantoínas/síntese química , Hidantoínas/farmacologia , Ligação de Hidrogênio , Imidazóis/síntese química , Imidazóis/farmacologiaRESUMO
A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2',3' or 2',5'-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRbeta over LXRalpha. The LXRbeta binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRalpha Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists.
Assuntos
Proteínas de Ligação a DNA/agonistas , Compostos Heterocíclicos com 2 Anéis/química , Quinolinas/química , Receptores Citoplasmáticos e Nucleares/agonistas , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Simulação por Computador , Proteínas de Ligação a DNA/metabolismo , Descoberta de Drogas , Humanos , Receptores X do Fígado , Camundongos , Receptores Nucleares Órfãos , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Relação Estrutura-AtividadeRESUMO
The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Benzoatos/síntese química , Fosfolipases A2 do Grupo IV/antagonistas & inibidores , Sulfonamidas/síntese química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Benzoatos/química , Benzoatos/farmacologia , Disponibilidade Biológica , Broncoconstrição/efeitos dos fármacos , Calorimetria , Carragenina , Linhagem Celular , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Masculino , Camundongos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ovinos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A series of potent and binding selective LXRbeta agonists was developed using the previously reported non-selective LXR ligand WAY-254011 as a structural template. With the aid of molecular modeling, it was found that 2,3-diMe-Ph, 2,5-diMe-Ph, and naphthalene substituted quinoline acetic acids (such as quinoline 33, 37, and 38) showed selectivity for LXRbeta over LXRalpha in binding assays.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Proteínas de Ligação a DNA/agonistas , Quinolinas/química , Quinolinas/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Ácidos Carboxílicos/farmacologia , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Humanos , Ligantes , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Receptores Nucleares Órfãos , Quinolinas/farmacologia , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Especificidade por Substrato , Ativação TranscricionalRESUMO
Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in sensory neurons where it functions as an irritant sensor for a plethora of electrophilic compounds and is implicated in pain, itch, and respiratory disease. To study its function in various disease contexts, we sought to identify novel, potent, and selective small-molecule TRPA1 antagonists. Herein we describe the evolution of an N-isopropylglycine sulfonamide lead (1) to a novel and potent (4 R,5 S)-4-fluoro-5-methylproline sulfonamide series of inhibitors. Molecular modeling was utilized to derive low-energy three-dimensional conformations to guide ligand design. This effort led to compound 20, which possessed a balanced combination of potency and metabolic stability but poor solubility that ultimately limited in vivo exposure. To improve solubility and in vivo exposure, we developed methylene phosphate prodrug 22, which demonstrated superior oral exposure and robust in vivo target engagement in a rat model of AITC-induced pain.
Assuntos
Pró-Fármacos/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Sulfonamidas/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidores , Animais , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Ligantes , Células Madin Darby de Rim Canino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Prolina/síntese química , Prolina/farmacocinética , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Canal de Cátion TRPA1/químicaRESUMO
NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTßR-dependent p52 translocation and transcription of NF-κB2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Quinase Induzida por NF-kappaBRESUMO
In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.
Assuntos
Anabolizantes/química , Androgênios/química , Nitrilas/química , Pirróis/química , Receptores Androgênicos/metabolismo , Anabolizantes/síntese química , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Androgênios/síntese química , Androgênios/farmacocinética , Androgênios/farmacologia , Animais , Cristalografia por Raios X , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Nitrilas/síntese química , Nitrilas/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos , Próstata/efeitos dos fármacos , Próstata/fisiologia , Pirróis/síntese química , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/fisiologia , Relação Estrutura-AtividadeRESUMO
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
Assuntos
Anticolesterolemiantes/síntese química , Aterosclerose/tratamento farmacológico , Proteínas de Ligação a DNA/agonistas , Fenilacetatos/síntese química , Quinolinas/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Colesterol/metabolismo , Proteínas de Ligação a DNA/genética , Estabilidade de Medicamentos , Feminino , Humanos , Técnicas In Vitro , Ligantes , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Receptores Nucleares Órfãos , Fenilacetatos/química , Fenilacetatos/farmacologia , Estrutura Terciária de Proteína , Quinolinas/química , Quinolinas/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Relação Estrutura-Atividade , Ativação TranscricionalRESUMO
The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.
Assuntos
Indazóis/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/toxicidade , Feminino , Humanos , Indazóis/farmacologia , Indazóis/toxicidade , Interleucina-13/biossíntese , Interleucina-2/biossíntese , Células Jurkat , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Sulfonas/toxicidade , Sulfóxidos/química , Sulfóxidos/farmacologia , Sulfóxidos/toxicidadeRESUMO
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Sulfonas/síntese química , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Animais , Bioensaio , Cartilagem/efeitos dos fármacos , Cartilagem/enzimologia , Bovinos , Diálise , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 13 da Matriz , Metaloendopeptidases/antagonistas & inibidores , Camundongos , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.0 microM) and did not recruit any coactivator/corepressor peptides in the LXRalpha multiplex assay. However, compound 13 showed good agonism in THP-1 cells with respect to increasing ABCA1 gene expression and good potency on cholesterol efflux in THP-1 foam cells. In an eight-week lesion study in LDLR -/- mice, compound 13 showed reduction of aortic arch lesion progression and no plasma or hepatic triglyceride increase. These results suggest quinoxaline 13 may have an improved biological profile for potential use as a therapeutic agent.
Assuntos
Receptores Nucleares Órfãos/agonistas , Quinoxalinas/síntese química , Sulfonas/síntese química , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Animais , Área Sob a Curva , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Linhagem Celular , Colesterol/metabolismo , Duodeno/metabolismo , Meia-Vida , Humanos , Rim/metabolismo , Fígado/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Especificidade de Órgãos , Receptores Nucleares Órfãos/genética , Quinoxalinas/química , Quinoxalinas/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Ativação Transcricional , Triglicerídeos/metabolismoAssuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/uso terapêutico , Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Obesidade/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A series of phenyl acetic acid based quinolines was prepared as LXR modulators. An SAR study in which the C-3 and C-8 positions of the quinoline core were varied led to the identification of two potent LXR agonists 23 and 27. Both compounds displayed good binding affinity for LXRbeta and LXRalpha, and increased expression of ABCA1 in THP-1 cells. These two compounds also had desirable pharmacokinetic profiles in mice and displayed in vivo efficacy in a 12-week Apo E knockout mouse lesion model.
Assuntos
Aterosclerose/prevenção & controle , Proteínas de Ligação a DNA/agonistas , Fenilacetatos/síntese química , Fenilacetatos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/patologia , Células CHO , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Cromatografia Líquida de Alta Pressão , Cricetinae , Cricetulus , Proteínas de Ligação a DNA/genética , Humanos , Indicadores e Reagentes , Receptores X do Fígado , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Nucleares Órfãos , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Recombinantes/metabolismo , Solventes , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Ativação Transcricional/genéticaRESUMO
We synthesized and evaluated a novel series of 2-carboxylic acid indole-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). Systematic modification of the N-1 position and the 5-position of the indole scaffold resulted in the identification of several compounds that showed good potency against PAI-1 in the spectrophotometric assay. This potency did not always translate to the antibody assay. Solubility and serum protein binding studies on selected analogs revealed that protein binding might be a factor in the poor correlation between the two assays.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Sítios de Ligação , Ácidos Carboxílicos , Ensaio de Imunoadsorção Enzimática , Espectrofotometria , Relação Estrutura-AtividadeRESUMO
A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate-enzyme interaction are disclosed herein.