RESUMEN
New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.
Asunto(s)
Isoquinolinas/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Quinazolinas/química , Receptor de Adenosina A2A/química , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Animales , Sitios de Unión , Diseño de Fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Ratas , Receptor de Adenosina A2A/metabolismo , Relación Estructura-ActividadRESUMEN
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Asunto(s)
Ácidos Carboxílicos/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Quinolonas/farmacología , Animales , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-ActividadRESUMEN
A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.
Asunto(s)
Amidas/química , Azoles/farmacología , Descubrimiento de Drogas , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Azoles/síntesis química , Azoles/química , Relación Dosis-Respuesta a Droga , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Conformación Molecular , Permeabilidad/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
Asunto(s)
Amidas/química , Diseño de Fármacos , Isoxazoles/química , Quinazolinonas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Perros , Semivida , Haplorrinos , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Ratas , Ratas Wistar , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Obesidad/tratamiento farmacológico , Animales , Antagonistas de los Receptores Histamínicos H3/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Receptores Histamínicos H3/metabolismoRESUMEN
The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
Asunto(s)
Amidas/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridinas/farmacología , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Inhibidores Enzimáticos/química , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.
Asunto(s)
Anilidas/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Lactamas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Anilidas/síntesis química , Anilidas/metabolismo , Unión Competitiva , Evaluación Preclínica de Medicamentos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lactamas/síntesis química , Lactamas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9µMh.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Cobayas , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Ratas , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Azepinas/síntesis química , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Animales , Azepinas/química , Azepinas/farmacología , Canal de Potasio ERG1 , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/química , Prolina/análogos & derivados , Quinolinas/síntesis química , Administración Oral , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Inhalación , Oxazoles/síntesis química , Oxazoles/farmacocinética , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacocinética , Prolina/síntesis química , Prolina/química , Prolina/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.
Asunto(s)
Azepinas/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Oxazocinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Azepinas/síntesis química , Azepinas/química , Humanos , Estructura Molecular , Oxazocinas/síntesis química , Oxazocinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.
Asunto(s)
Química Farmacéutica/métodos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacocinética , Tiadiazoles/farmacología , Administración Oral , Animales , Cetonas , Obesidad/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Asunto(s)
Antiinflamatorios/síntesis química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/síntesis química , Inhibidores de Fosfodiesterasa 4/síntesis química , Quinolinas/síntesis química , Animales , Antiinflamatorios/farmacología , Óxidos N-Cíclicos/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Oxazoles/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/agonistas , Sulfuros/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Disponibilidad Biológica , Línea Celular , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Conformación Molecular , Ratas , Ratas Endogámicas BN , Receptores de Glucocorticoides/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/administración & dosificación , Sulfuros/química , Tirosina Transaminasa/metabolismoRESUMEN
Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.
Asunto(s)
Éteres/farmacología , Lactonas/farmacología , Pirimidinas/farmacología , Receptores Nicotínicos/metabolismo , Éteres/síntesis química , Éteres/química , Humanos , Lactonas/síntesis química , Lactonas/química , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.
Asunto(s)
Receptores de Glucocorticoides/efectos de los fármacos , Esteroides/química , Sulfuros/química , Humanos , Hidrocortisona , Pirazoles/química , Relación Estructura-Actividad , Sulfuros/farmacología , Activación Transcripcional/efectos de los fármacosRESUMEN
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.