RESUMO
Induction of cytochrome P450 isoform 3A4 via activation of the pregnane xenobiotic receptor (PXR) is a concern for pharmaceutical discovery and development, as it can lead to drug-drug interactions. We present a novel molecular descriptor, the smallest maximum intramolecular distance (SMID), which is correlated with PXR activation, and a method for using the SMID descriptor to guide discovery chemists in modifying lead compounds to decrease PXR activation.
Assuntos
Receptores de Esteroides , Citocromo P-450 CYP3A , Interações Medicamentosas , Receptor de Pregnano X , Pregnanos , Xenobióticos/toxicidadeRESUMO
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
Assuntos
Anti-Hipertensivos/farmacologia , Citocromo P-450 CYP11B2/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Indazóis/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Linhagem Celular , Cricetulus , Inibidores do Citocromo P-450 CYP2D6/síntese química , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Macaca mulatta , Masculino , Ratos Sprague-Dawley , Estereoisomerismo , Esteroide 11-beta-Hidroxilase/antagonistas & inibidoresRESUMO
Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic ß-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/química , Ativadores de Enzimas/uso terapêutico , Glucoquinase/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Indóis/química , Indóis/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/farmacologia , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Insulina/sangue , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hipoglicemiantes/farmacologia , Piridinas/farmacologia , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Descoberta de Drogas , Ativadores de Enzimas/química , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Piridinas/química , Piridinas/farmacocinética , Piridinas/uso terapêuticoRESUMO
During drug development, compounds are tested against counterscreens, a panel of off-target activities that would be undesirable for a drug to have. Testing every compound against every counterscreen is generally too costly in terms of time and money, and we need to find a rational way of prioritizing counterscreen testing. Here we present the eCounterscreening paradigm, wherein predictions from QSAR models for counterscreen activity are used to generate a recommendation as to whether a specific compound in a specific project should be tested against a specific counterscreen. The rules behind the recommendations, which can be summarized in a risk-benefit plot specific for a counterscreen/project combination, are based on a previously assembled database of prospective QSAR predictions. The recommendations require two user-defined cutoffs: the level of activity in a specific counterscreen that is considered undesirable and the level of risk the chemist is willing to accept that an undesired counterscreen activity will go undetected. We demonstrate in a simulated prospective experiment that eCounterscreening can be used to postpone a large fraction of counterscreen testing and still have an acceptably low risk of undetected counterscreen activity.
Assuntos
Ensaios de Triagem em Larga Escala/métodos , Relação Quantitativa Estrutura-Atividade , Algoritmos , Mineração de Dados , Bases de Dados Factuais , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Modelos Químicos , Valor Preditivo dos Testes , Medição de RiscoRESUMO
Small interfering RNAs (siRNAs) are short, double-stranded RNAs that use the endogenous RNAi pathway to mediate gene silencing. Phosphorylation facilitates loading of a siRNA into the Ago2 complex and subsequent cleavage of the target mRNA. In this study, 2', 3' seco nucleoside modifications, which contain an acylic ribose ring and are commonly called unlocked nucleic acids (UNAs), were evaluated at all positions along the guide strand of a siRNA targeting apolipoprotein B (ApoB). UNA modifications at positions 1, 2 and 3 were detrimental to siRNA activity. UNAs at positions 1 and 2 prevented phosphorylation by Clp1 kinase, abrogated binding to Ago2, and impaired Ago2-mediated cleavage of the mRNA target. The addition of a 5'-terminal phosphate to siRNA containing a position 1 UNA restored ApoB mRNA silencing, Ago2 binding, and Ago2 mediated cleavage activity. Position 1 UNA modified siRNA containing a 5'-terminal phosphate exhibited a partial restoration of siRNA silencing activity in vivo. These data reveal the complexity of interpreting the effects of chemical modification on siRNA activity, and exemplify the importance of using multiple biochemical, cell-based and in vivo assays to rationally design chemically modified siRNA destined for therapeutic use.
Assuntos
Nucleosídeos/química , Interferência de RNA , RNA Interferente Pequeno/química , Animais , Apolipoproteínas B/genética , Linhagem Celular , Fator de Iniciação 2 em Eucariotos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Fosforilação , Fosfotransferases/metabolismo , RNA Interferente Pequeno/metabolismo , Termodinâmica , Fatores de Transcrição/metabolismo , Pequeno RNA não TraduzidoRESUMO
A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.
Assuntos
Antitrombinas/síntese química , Benzeno/síntese química , Desenho de Fármacos , Trombina/antagonistas & inibidores , Antitrombinas/química , Antitrombinas/farmacologia , Benzeno/química , Benzeno/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Niemann-Pick C1-like protein (NPC1L1) mediates the absorption of dietary cholesterol in the proximal region of the intestine, a process that is blocked by cholesterol absorption inhibitors (CAIs), including ezetimibe (EZE). Using a proteomic approach, we demonstrate that NPC1L1 is the protein to which EZE and its analogs bind. Next, we determined the site of interaction of EZE analogs with NPC1L1 by exploiting the different binding affinities of mouse and dog NPC1L1 for the radioligand analog of EZE, [(3)H]AS. Chimeric and mutational studies indicate that high-affinity binding of [(3)H]AS to dog NPC1L1 depends on molecular determinants present in a 61-aa region of a large extracellular domain (loop C), where Phe-532 and Met-543 appear to be key contributors. These data suggest that the [(3)H]AS-binding site resides in the intestinal lumen and are consistent with preclinical data demonstrating in vivo efficacy of a minimally bioavailable CAI. Furthermore, these determinants of [(3)H]AS binding lie immediately adjacent to a hotspot of human NPC1L1 polymorphisms correlated with hypoabsorption of cholesterol. These observations, taken together with the recently described binding of cholesterol to the N terminus (loop A) of the close NPC1L1 homologue, NPC1, may provide a molecular basis for understanding EZE inhibition of NPC1L1-mediated cholesterol absorption. Specifically, EZE binding to an extracellular site distinct from where cholesterol binds prevents conformational changes in NPC1L1 that are necessary for the translocation of cholesterol across the membrane.
Assuntos
Anticolesterolemiantes/farmacologia , Azetidinas/farmacologia , Colesterol na Dieta/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Transporte Biológico Ativo/efeitos dos fármacos , Transporte Biológico Ativo/genética , Linhagem Celular , Membrana Celular/genética , Membrana Celular/metabolismo , Cães , Ezetimiba , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/genética , Proteínas de Membrana Transportadoras/genética , Camundongos , Mutação , Polimorfismo Genético , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Estrutura Secundária de Proteína/genética , Estrutura Terciária de Proteína/genética , Proteômica/métodosRESUMO
Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-ß-lactams can be effective CAIs.
Assuntos
Anticolesterolemiantes/síntese química , Imidazóis/síntese química , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Azetidinas , Ezetimiba , Imidazóis/química , Imidazóis/farmacologia , Absorção Intestinal/efeitos dos fármacos , Camundongos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of spiroimidazolidinone NPC1L1 inhibitors was discovered by virtual screening of the Merck corporate sample repository using 3D-similarity-based screening. Selection of 330 compounds for testing in an in vitro NPC1L1 binding assay yielded six hits in six distinct chemical series. Follow-up 2D similarity searching yielded several sub- to low-micromolar leads; among these was spiroimidazolidinone 10, with an IC(50) of 2.5 microM. Compound 10 provided a useful scaffold to initiate a medicinal chemistry campaign.
Assuntos
Anticolesterolemiantes/química , Imidazolidinas/química , Proteínas de Membrana/antagonistas & inibidores , Compostos de Espiro/química , Animais , Anticolesterolemiantes/farmacologia , Cricetinae , Cães , Desenho de Fármacos , Cobaias , Humanos , Imidazolidinas/farmacologia , Macaca mulatta , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Modelos Químicos , Conformação Molecular , Ratos , Software , Compostos de Espiro/farmacologia , SuínosRESUMO
A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na(v)1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na(v)1.7 inhibitory activity.
Assuntos
Isoxazóis/uso terapêutico , Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/metabolismo , Animais , Linhagem Celular , Doença Crônica , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Dor/imunologia , Ratos , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Nervos Espinhais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Analogs of the previously reported voltage gated sodium channel blocker CDA54 were prepared in which one of the amide functions was replaced with aromatic and non-aromatic heterocycles. Replacement of the amide with an aromatic heterocycle resulted in significant loss of sodium channel blocking activity, while non-aromatic heterocycle replacements were well tolerated.
Assuntos
Isoxazóis/química , Isoxazóis/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Isoxazóis/uso terapêutico , Modelos Moleculares , Estrutura Molecular , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/uso terapêutico , Nervos Espinhais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.
Assuntos
Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Trombina/antagonistas & inibidores , Administração Oral , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacocinética , Antitrombinas/síntese química , Antitrombinas/química , Antitrombinas/farmacocinética , Disponibilidade Biológica , Cloretos , Cristalografia por Raios X , Cães , Compostos Férricos/farmacologia , Imidazóis/química , Imidazóis/farmacocinética , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Tempo de Tromboplastina Parcial , Ratos , Relação Estrutura-Atividade , Trombina/química , Trombina/metabolismo , Tripsina/metabolismoRESUMO
Selective binding of a drug for its target vs other proteins is an important consideration in designing compounds with minimal risk of toxicity and therefore a key aspect of lead optimization. Screening all compounds against all known off-target proteins would be prohibitively expensive, so project teams must decide which compounds to screen in which assays. This chapter describes informatics-based methods that help prioritize testing, including screening minipanels and prioritization using predictive models (e-counterscreening).
Assuntos
Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Animais , Humanos , Terapia de Alvo Molecular , Proteínas/metabolismo , Relação Quantitativa Estrutura-AtividadeRESUMO
Aldehyde oxidase is a molybdenum hydroxylase that catalyzes the oxidation of aldehydes and nitrogen-containing heterocycles. The enzyme plays a dual role in the metabolism of physiologically important endogenous compounds and the biotransformation of xenobiotics. Using density functional theory methods, geometry optimization of tetrahedral intermediates of drugs and druglike compounds was examined to predict the likely metabolites of aldehyde oxidase. The calculations suggest that the lowest energy tetrahedral intermediate resulting from the initial substrate corresponds to the observed metabolite >or=90% of the time. Additional calculations were performed on a series of heterocyclic compounds where the products resulting from metabolism by xanthine oxidase and aldehyde oxidase differ in many instances. Again, the lowest energy tetrahedral intermediate corresponded to the observed product of aldehyde oxidase metabolism >or=90% for the compounds examined, while the observed products of xanthine oxidase were not well predicted.
Assuntos
Aldeído Oxidase/química , Modelos Moleculares , Preparações Farmacêuticas/química , Relação Quantitativa Estrutura-Atividade , Aldeído Oxidase/metabolismo , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Preparações Farmacêuticas/metabolismo , Estereoisomerismo , Termodinâmica , Xantina Oxidase/química , Xantina Oxidase/metabolismoRESUMO
The affinities of a diverse set of 500 drug-like molecules to cytochrome P450 isoforms 2C9 and 2D6 were measured using recombinant expressed enzyme. The dose-response curve of each compound was fitted with a series of equations representing typical or various types of atypical kinetics. Atypical kinetics was identified where the Akaike Information Criterion, plus other criteria, suggested the kinetics was more complex than expected for a Michaelis-Menten model. Approximately 20% of the compounds were excluded due to poor solubility, and approximately 15% were excluded due to fluorescence interference. Of the remaining compounds, roughly half were observed to bind with an affinity of 200 microM or lower for each of the two isoforms. Atypical kinetics was observed in 18% of the compounds that bind to cytochrome 2C9, but less than 2% for 2D6. The resulting collection of competitive inhibitors and inactive compounds were analyzed for trends in binding affinity. For CYP2D6, a clear relationship between polar surface area and charge was observed, with the most potent inhibitors having a formal positive charge and a low percent polar surface area. For CYP2C9, no clear trend between activity and physicochemical properties could be seen for the group as a whole; however, certain classes of compounds have altered frequencies of activity and atypical kinetics.
Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Inibidores do Citocromo P-450 CYP2D6 , Inibidores Enzimáticos/farmacologia , Citocromo P-450 CYP2C9 , Inibidores Enzimáticos/química , Fluorescência , Cinética , Relação Quantitativa Estrutura-Atividade , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.
RESUMO
The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V(600E)) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAF(V600) (E)-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G(186D)) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548-59. ©2016 AACR.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , RatosRESUMO
Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.
Assuntos
Fluorenos/síntese química , Prolina/análogos & derivados , Prolina/síntese química , Trombina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Cristalografia por Raios X , Cães , Fluorenos/química , Fluorenos/farmacologia , Meia-Vida , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Prolina/química , Prolina/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.