RESUMO
GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.
Assuntos
Compostos Aza/química , Inibidores Enzimáticos/química , Quinolinas/química , Animais , Sítios de Ligação , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Estabilidade de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/metabolismo , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models.
Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Amidas/química , Inibidores Enzimáticos/química , NAD/metabolismo , Quinazolinas/química , ADP-Ribosil Ciclase 1/metabolismo , Amidas/metabolismo , Amidas/farmacocinética , Animais , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Camundongos , Simulação de Acoplamento Molecular , NAD/química , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.
Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Amidas/química , Aminoquinolinas/química , NAD/metabolismo , Quinolinas/química , Amidas/síntese química , Amidas/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/farmacologia , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Hidrólise , Fígado/metabolismo , Membranas Artificiais , Camundongos Endogâmicos C57BL , Modelos Moleculares , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Permeabilidade , Conformação Proteica , Quinolinas/síntese química , Quinolinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.
Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Quinolonas/química , Quinolonas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , ADP-Ribosil Ciclase 1/metabolismo , Animais , Linhagem Celular , Cães , Descoberta de Drogas , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Músculos/efeitos dos fármacos , Músculos/metabolismo , NAD/análise , NAD/sangue , NAD/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Quinolonas/síntese química , Quinolonas/farmacocinética , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas , PPAR gama/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , PPAR gama/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
Assuntos
Acetatos/química , PPAR delta/agonistas , Acetatos/síntese química , Acetatos/farmacocinética , Animais , Sítios de Ligação , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , PPAR delta/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.
Assuntos
Benzamidas/síntese química , PPAR delta/antagonistas & inibidores , Sulfonas/síntese química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzamidas/farmacocinética , Benzamidas/farmacologia , Sítios de Ligação , Carnitina O-Palmitoiltransferase/biossíntese , Carnitina O-Palmitoiltransferase/genética , Linhagem Celular Tumoral , Cisteína/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Genes Reporter , Humanos , Ligantes , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/enzimologia , PPAR delta/agonistas , PPAR delta/genética , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologia , Distribuição Tecidual , Transcrição Gênica/efeitos dos fármacosRESUMO
Anthranilic acid GW9371 was identified as a novel class of PPARdelta partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARdelta target genes CPT1a and PDK4 in skeletal muscle cells.
Assuntos
PPAR delta/agonistas , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Técnicas de Química Combinatória , Cristalografia por Raios X , Humanos , Estrutura Molecular , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , ortoaminobenzoatos/químicaRESUMO
The identification of small molecule ligands for the peroxisome proliferator-activated receptors (PPARs) has been instrumental in elucidating their biological roles. In particular, agonists have been the focus of much of the research in the field with relatively few antagonists being described and all of those being selective for PPARalpha or PPARgamma. The comparison of these agonist and antagonist ligands in cellular and animal systems has often led to surprising results and new insights into the biology of the PPARs. The PPARbeta/delta receptor is emerging as an important regulator of energy metabolism, inflammation, and cell growth and differentiation; however, only agonist ligands have been described for this receptor thus far. Here we describe the first report of a PPARbeta/delta small molecule antagonist ligand. This antagonist ligand will be a useful tool for elucidating the biological roles of PPARbeta/delta.
Assuntos
Ligantes , PPAR delta/antagonistas & inibidores , PPAR beta/antagonistas & inibidores , Células Cultivadas , Imunoprecipitação da Cromatina , Relação Dose-Resposta a Droga , Ácidos Graxos/metabolismo , Transferência Ressonante de Energia de Fluorescência , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução/efeitos dos fármacos , Sulfonas/química , Sulfonas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Agonists of PPARalpha and PPARgamma are currently approved for use in treating, respectively, dyslipidemia and type 2 diabetes. Agonists of PPARbeta/delta are currently in development by several pharmaceutical companies. Despite their therapeutic importance, there are dose limiting side effects associated with PPAR drug treatments, thus a new generation of safer PPAR drugs are being actively sought after. In this review we will discuss the side effects associated the PPARs, how the current drugs in clinical development were discovered and new concepts in how to screen for PPAR drugs.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Desenho de Fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , PPAR alfa/agonistas , PPAR gama/agonistas , SegurançaRESUMO
The design, synthesis, and SAR of a novel series of heterobiaryl phenethanolamine beta3 adrenergic receptor agonists are described. The furan analogue 49 was shown to elicit a significant dose-dependent lowering of plasma glucose in a rodent model of type 2 diabetes.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Sítios de Ligação , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
PPARgamma-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPARgamma rich adipose. Both pro- and anti-adipogenic PPARgamma ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPARgamma in mature adipocytes.
Assuntos
Oxazóis/farmacologia , PPAR gama/antagonistas & inibidores , Tirosina/análogos & derivados , Cristalização , Ligantes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Oxazóis/química , PPAR gama/metabolismo , Tirosina/química , Tirosina/farmacologiaRESUMO
The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Compostos de Anilina/química , Etanolamina/química , Etanolamina/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Animais , Glicemia/metabolismo , Linhagem Celular , Cricetinae , AMP Cíclico/metabolismo , Cães , Etanolamina/síntese química , Glicosilação/efeitos dos fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1alpha in activation of human ERRbeta and ERRgamma.
Assuntos
Receptor beta de Estrogênio/agonistas , Hidrazinas/síntese química , Fenóis/síntese química , Receptores de Estrogênio/agonistas , Ligação Competitiva , Receptor beta de Estrogênio/genética , Transferência Ressonante de Energia de Fluorescência , Genes Reporter , Células HeLa , Proteínas de Choque Térmico/biossíntese , Humanos , Hidrazinas/química , Hidrazinas/farmacologia , Ligantes , Mimetismo Molecular , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fenóis/química , Fenóis/farmacologia , Receptores de Estrogênio/genética , Relação Estrutura-Atividade , Fatores de Transcrição/biossínteseRESUMO
The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors, a set of three receptor sub-types encoded by distinct genes, function as lipid sensors to regulate a broad range of genes in many metabolically active tissues. Synthetic PPAR agonists have exhibited therapeutic benefits in treating diabetes and cardiovascular diseases. The discovery of PPAR-specific ligands has led to significant advancement in our understanding of the structure of these receptor proteins and the molecular mechanism of their ligand-dependent activation. Herein, we present both recent progress in the functional analysis of these orphan receptors and the confirmation of the PPARs as molecular targets for the development of new medicines to treat human metabolic disease.
Assuntos
Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Tecnologia Farmacêutica/tendências , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Humanos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Fatores de Transcrição/agonistas , Fatores de Transcrição/antagonistas & inibidoresRESUMO
A solid-phase synthesis of substituted benzopyranoisoxazoles is described. The six-step synthesis features a novel method of generating nitrile oxides on a polymer support followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne for assembly of the benzopyranoisoxazole scaffold. Furthermore, the utilization of single-bead attenuated total reflectance Fourier transform infrared (ATR-IR) microspectroscopy as an essential analytical tool for reaction optimization is highlighted.
RESUMO
Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR, which in turn recruit histone deacetylases to the chromatin. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists. Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. In this structure, the co-repressor motif adopts a three-turn alpha-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation. Binding of the co-repressor motif is further reinforced by the antagonist, which blocks the AF-2 helix from adopting the active position. Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors.