RESUMEN
GSK2798745, an antagonist of the transient receptor potential vanilloid 4 (TRPV4) ion channel, was recently investigated in clinical trials for the treatment of cardiac and respiratory diseases. Human plasma and urine samples collected from healthy volunteers following oral administration were analyzed to identify circulating and excreted metabolites of the parent drug. One major circulating metabolite (1) was found in pooled human plasma samples, accounting for approximately half of the observed drug-related material. Isolation of metabolite 1 from urine samples followed by MS and NMR studies led to a putative structural assignment of 1 where hydroxylation of GSK2798745 occurred on the central ring, producing a penta-substituted cyclohexane structure containing three stereocenters. Two unique chemical syntheses of the proposed structure were developed to confirm the identity of metabolite 1 and provide access to gram quantities for biological characterization.
RESUMEN
Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold hopping approach, which relied on use of an internal H-bond to replace a saturated heterocyclic ring. Optimization of the lead through investigation of both aryl regions revealed approaches to increase potency through substituents believed to enhance separate intramolecular and intermolecular H-bond interactions. A proposed internal H-bond between the amine and neighboring benzenesulfonamide was stabilized by electronically modulating the benzenesulfonamide. In the aryl ether moiety, substituents para to the nitrile demonstrated an electronic effect on TRPV4 recognition. Finally, the acyclic amines inactivated CYP3A4 and this liability was addressed by modifications that sterically preclude formation of a putative metabolic intermediate complex to deliver advanced TRPV4 antagonists as leads for discovery of novel medicines.
Asunto(s)
Diaminas/química , Sulfonamidas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Citocromo P-450 CYP3A/metabolismo , Diaminas/síntesis química , Diaminas/metabolismo , Diaminas/farmacocinética , Diseño de Fármacos , Humanos , Enlace de Hidrógeno/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Canales Catiónicos TRPV/química , Canales Catiónicos TRPV/metabolismoRESUMEN
GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.
Asunto(s)
Pirrolidinas/química , Sulfonamidas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Pirrolidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110ß. FMRP deficiency increases p110ß protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110ß-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110ß-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110ß inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Ratones , Actividad Motora/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
Asunto(s)
Edema Pulmonar/tratamiento farmacológico , Pirrolidinas/farmacología , Sulfonamidas/farmacología , Sulfonas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/química , Sulfonas/farmacocinéticaRESUMEN
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tiazoles/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
A series of novel [3a,4]dihydropyrazolo[1,5a]pyrimidines were identified, which were highly potent and selective inhibitors of PI3Kß. The template afforded the opportunity to develop novel SAR for both the hinge-binding (R3) and back-pocket (R4) substitutents. While cellular potency was relatively modest due to high protein binding, the series displayed low clearance in rat, mouse, and monkey.
RESUMEN
A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (â¼ 0.100 µM IC(50)) growth inhibition in a PTEN deficient cancer cell line.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Fosfohidrolasa PTEN/deficiencia , Isoformas de Proteínas/antagonistas & inhibidores , Pirimidinas , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.
Asunto(s)
Antineoplásicos/síntesis química , Imidazoles/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinonas/síntesis química , Antineoplásicos/farmacología , Sitios de Unión , Neoplasias de la Mama , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Eliminación de Gen , Humanos , Imidazoles/farmacología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Cinética , Modelos Moleculares , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinonas/farmacología , Relación Estructura-ActividadRESUMEN
A novel thiazolopyrimidinone series of PI3K-beta selective inhibitors has been identified. This chemotype has provided an excellent tool compound, 18, that showed potent growth inhibition in the PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage-independent conditions, and it also demonstrated pharmacodynamic effects and efficacy in a PTEN-deficient prostate cancer PC-3 xenograft mouse model.
RESUMEN
Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.
Asunto(s)
Amidas/síntesis química , Amidas/farmacocinética , Hidrocarburos Aromáticos/síntesis química , Hidrocarburos Aromáticos/farmacocinética , Receptor Muscarínico M1/agonistas , Amidas/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Sistema Nervioso Central/metabolismo , Descubrimiento de Drogas , Hidrocarburos Aromáticos/farmacología , Estructura Molecular , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described.
Asunto(s)
Amidas/síntesis química , Hidrocarburos Aromáticos/síntesis química , Receptor Muscarínico M1/agonistas , Amidas/farmacología , Descubrimiento de Drogas , Hidrocarburos Aromáticos/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of potent exemplars (up to pEC50=9). Details of the SAR and optimization of this series are presented herein.
Asunto(s)
Acrilamidas/síntesis química , Diseño de Fármacos , Isoxazoles/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Acrilamidas/química , Acrilamidas/farmacología , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.
RESUMEN
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.
Asunto(s)
Isoxazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Perros , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/administración & dosificación , Humanos , Isoxazoles/química , Isoxazoles/farmacocinética , RatasRESUMEN
Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.
Asunto(s)
Aminas/síntesis química , Química Farmacéutica/métodos , Receptor Muscarínico M3/antagonistas & inhibidores , Amidas/química , Aminas/farmacología , Asma/tratamiento farmacológico , Diseño de Fármacos , Electrones , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Estructura Molecular , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptor Muscarínico M3/química , Relación Estructura-ActividadRESUMEN
A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described.
Asunto(s)
Alcanfor/análogos & derivados , Receptores CXCR3/antagonistas & inhibidores , Sulfonamidas/síntesis química , Alcanfor/síntesis química , Alcanfor/farmacología , Humanos , Piperazinas , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
Asunto(s)
Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacología , Piperazinas/farmacología , Receptores Muscarínicos/efectos de los fármacos , Administración Intranasal , Animales , Pruebas de Provocación Bronquial , Broncoconstrictores/farmacología , Broncodilatadores/síntesis química , Broncodilatadores/química , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Cloruro de Metacolina/farmacología , Ratones , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
High throughput screening of our compound collection led to the discovery of a novel series of N-alkyl-5H-pyrido[4,3-b]indol-1-amines as urotensin-II receptor antagonists. Synthesis, initial structure and activity relationships, functional and animal ortholog activities of the series are described.