RESUMO
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.
Assuntos
Amidas/farmacologia , Descoberta de Drogas , Pirazóis/farmacologia , Receptores CCR1/antagonistas & inibidores , Amidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirazóis/química , Receptores CCR1/metabolismo , Relação Estrutura-AtividadeRESUMO
Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.
Assuntos
Compostos Aza/farmacologia , Indazóis/farmacologia , Receptores CCR1/antagonistas & inibidores , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Indazóis/síntese química , Indazóis/química , Estrutura Molecular , Receptores CCR1/metabolismo , 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 arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.
Assuntos
Receptores de Glucocorticoides/agonistas , Esteroides/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sítios de Ligação , Glucocorticoides/química , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismoRESUMO
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
Inhibition of sEH is hypothesized to lead to an increase in epoxyeicosatrienoic acids resulting in the potentiation of their anti-inflammatory and vasodilatory effects. In an effort to explore sEH inhibition as an avenue for the development of vasodilatory and cardio- or renal-protective agents, a lead identified through high-throughput screening was optimized, guided by the determination of a solid state co-structure with sEH. Replacement of potential toxicophores was followed by optimization of cell-based potency and ADME properties to provide a new class of functionally potent sEH inhibitors with attractive in vitro metabolic profiles and high and sustained plasma exposures after oral administration in the rat.
Assuntos
Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Piperidinas/química , Ureia/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Ureia/química , Ureia/farmacocinéticaRESUMO
A 270-membered library of trisubstituted ureas was synthesized and evaluated for inhibition of soluble epoxide hydrolase. Library design and reagent selection was guided by the use of a pharmacophore model and synthesis of the array was enabled with a general solid-phase method. This array approach facilitated multi-dimensional SAR around this series and identified functionality responsible for binding affinity, as well as opportunities for modulating the overall in vitro profiles of this class of soluble epoxide hydrolase inhibitors.
Assuntos
Técnicas de Química Combinatória/métodos , Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Ureia/análogos & derivados , Animais , Humanos , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade , Ureia/químicaRESUMO
A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.
Assuntos
Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Pirazóis/farmacologia , Células CACO-2 , Domínio Catalítico , Cristalografia por Raios X , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos MolecularesRESUMO
A series of potent nicotinamide inhibitors of soluble epoxides hydrolase (sEH) is disclosed. This series was designed using structure-based deconstruction and a combination of two HTS hit series, resulting in hybrid analogs that retained the optimal potency from one series, and acceptable in vitro metabolic stability from the other. Structure-guided optimization of these analogs gave rise to nanomolar inhibitors of human sEH that had acceptable plasma exposure to qualify them as probes to determine the in vivo phenotypic consequences of sEH inhibition.
Assuntos
Anti-Inflamatórios/síntese química , Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Niacinamida/síntese química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Niacinamida/química , Niacinamida/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.
Assuntos
Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Sulfonamidas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/química , Animais , Sítios de Ligação , Disponibilidade Biológica , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Niacinamida/análogos & derivados , Niacinamida/síntese química , Niacinamida/química , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
We report on the nuclear receptor binding affinities, cellular activities of transrepression and transactivation, and anti-inflammatory properties of a quinol-4-one and other A-ring mimetic containing nonsteroidal class of glucocorticoid agonists.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Glucocorticoides/agonistas , Mimetismo Molecular , Quinolonas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Transativadores/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Aromatase/metabolismo , Dexametasona/farmacologia , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células HeLa , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Quinolonas/síntese química , Quinolonas/química , Transativadores/síntese química , Transativadores/química , Ativação TranscricionalRESUMO
Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.
Assuntos
Osso e Ossos/efeitos dos fármacos , Receptores de Glucocorticoides/agonistas , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Relação Estrutura-AtividadeRESUMO
A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.
RESUMO
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
Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.
Assuntos
Epóxido Hidrolases/antagonistas & inibidores , Niacinamida/análogos & derivados , Administração Oral , Animais , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Ratos , SolubilidadeRESUMO
A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.
Assuntos
Glucocorticoides/agonistas , Ligantes , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.