RESUMEN
Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Compuestos Aza/química , Inhibidores Enzimáticos/química , Quinolinas/química , Animales , Sitios de Unión , Encéfalo/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Estabilidad de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación de Dinámica Molecular , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50â¯=â¯220,000â¯nM, LEâ¯=â¯0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50â¯=â¯3,100â¯nM, LEâ¯=â¯0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50â¯=â¯9.9â¯nM, LEâ¯=â¯0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Lipocalinas/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Humanos , Oxidorreductasas Intramoleculares/química , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/química , Lipocalinas/metabolismo , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Quinolinas/farmacocinéticaRESUMEN
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.
Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Amidas/química , Inhibidores Enzimáticos/química , NAD/metabolismo , Quinazolinas/química , ADP-Ribosil Ciclasa 1/metabolismo , Amidas/metabolismo , Amidas/farmacocinética , Animales , Sitios de Unión , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Ratones , Simulación del Acoplamiento Molecular , NAD/química , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Amidas/química , Aminoquinolinas/química , NAD/metabolismo , Quinolinas/química , Amidas/síntesis química , Amidas/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Humanos , Hidrólisis , Hígado/metabolismo , Membranas Artificiales , Ratones Endogámicos C57BL , Modelos Moleculares , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Permeabilidad , Conformación Proteica , Quinolinas/síntesis química , Quinolinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Quinolonas/química , Quinolonas/farmacología , Tiazoles/química , Tiazoles/farmacología , ADP-Ribosil Ciclasa 1/metabolismo , Animales , Línea Celular , Perros , Descubrimiento de Drogas , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Músculos/efectos de los fármacos , Músculos/metabolismo , NAD/análisis , NAD/sangre , NAD/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Quinolonas/síntesis química , Quinolonas/farmacocinética , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Oxazolidinonas/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Evaluación Preclínica de Medicamentos , Transferencia Resonante de Energía de Fluorescencia , Humanos , Modelos Moleculares , Estructura Molecular , Oxazolidinonas/química , Relación Estructura-ActividadRESUMEN
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Estilbenos/química , Estilbenos/farmacología , Secuencia de Aminoácidos , Animales , Línea Celular , Humanos , Conformación Molecular , Datos de Secuencia Molecular , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Sitios de Unión , Glucemia/metabolismo , Cristalografía por Rayos X , Diabetes Mellitus Experimental/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ligandos , Ratones , Conformación Molecular , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Isoxazoles/farmacología , Naftalenos/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Asunto(s)
Isoxazoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Isoxazoles/química , Isoxazoles/farmacología , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists.
Asunto(s)
Omeprazol/química , Receptores de Bombesina/agonistas , Baculoviridae/metabolismo , Bencimidazoles/química , Encéfalo/metabolismo , Química Farmacéutica/métodos , Clorofluorocarburos de Metano/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Cinética , Modelos Químicos , Piridinas/química , Receptores de Bombesina/química , Sulfuros/químicaRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Colestasis/tratamiento farmacológico , Proteínas de Unión al ADN/agonistas , Isoxazoles/síntesis química , Isoxazoles/farmacología , Naftalenos/síntesis química , Naftalenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Administración Oral , Animales , Ácidos Carboxílicos/química , Colestasis/metabolismo , Colestasis/patología , Cristalografía por Rayos X , Proteínas de Unión al ADN/química , Modelos Animales de Enfermedad , Perros , Mucosa Gástrica/metabolismo , Haplorrinos , Isoxazoles/química , Ratones , Conformación Molecular , Estructura Molecular , Naftalenos/química , Ratas , Receptores Citoplasmáticos y Nucleares/química , Estómago/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/químicaRESUMEN
Explorations of the S(1') subsite of ACE2 via modifications of the P(1') methylene biphenyl moiety of thiol-based metalloprotease inhibitors led to improvements in ACE2 selectivity versus ACE and NEP, while maintaining potent ACE2 inhibition.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Peptidil-Dipeptidasa A/metabolismo , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacología , Enzima Convertidora de Angiotensina 2 , Sitios de Unión , Humanos , Modelos Moleculares , Estructura Molecular , Proteínas Recombinantes , Relación Estructura-ActividadRESUMEN
Screening of a metalloprotease library led to the identification of a thiol-based dual ACE/NEP inhibitor as a potent ACE2 inhibitor. Modifications of the P(1) benzyl moiety led to improvements in ACE2 potency as well as to increased selectivity versus ACE and NEP.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Peptidil-Dipeptidasa A/efectos de los fármacos , Compuestos de Sulfhidrilo/química , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Peptidil-Dipeptidasa A/genética , Relación Estructura-Actividad , Especificidad por Sustrato , Compuestos de Sulfhidrilo/metabolismo , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
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.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Sitios de Unión , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Cetonas/química , Cetonas/farmacocinética , Administración Oral , Disponibilidad Biológica , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/administración & dosificación , Humanos , Cetonas/administración & dosificación , Conformación Proteica , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Compuestos de Anilina/química , Etanolamina/química , Etanolamina/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Animales , Glucemia/metabolismo , Línea Celular , Cricetinae , AMP Cíclico/metabolismo , Perros , Etanolamina/síntesis química , Glicosilación/efectos de los fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Asunto(s)
Amidas , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa , Cetonas , Pirrolidinas , Amidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Sitios de Unión , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Humanos , Concentración 50 Inhibidora , Cetonas/síntesis química , Cetonas/farmacocinética , Cetonas/farmacología , Modelos Moleculares , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Inhibidores de Serina Proteinasa , Relación Estructura-ActividadRESUMEN
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.