RESUMEN
Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.
Asunto(s)
Acetamidas/síntesis química , Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/síntesis química , Pirimidinas/síntesis química , Acetamidas/farmacocinética , Acetamidas/farmacología , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Catalepsia/inducido químicamente , Catalepsia/psicología , Línea Celular , Clonación Molecular , Cricetinae , Cricetulus , Haloperidol , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Receptor de Adenosina A2A/genética , Solubilidad , Relación Estructura-Actividad , AguaRESUMEN
Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Antagonistas del Receptor de Adenosina A2 , Pirimidinas/síntesis química , Pirimidinas/farmacología , Acetamidas/química , Animales , Sitios de Unión , Ciclización , Evaluación Preclínica de Medicamentos , Hepatocitos/efectos de los fármacos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirimidinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
Asunto(s)
Acetamidas/farmacología , Antagonistas del Receptor de Adenosina A2 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Pirimidinas/farmacología , Acetamidas/síntesis química , Acetamidas/química , Antagonistas del Receptor de Adenosina A1 , Animales , Evaluación Preclínica de Medicamentos , Canales de Potasio Éter-A-Go-Go/metabolismo , Hepatocitos/efectos de los fármacos , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Ratas Wistar , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/síntesis química , Catalepsia/prevención & control , Enfermedad de Parkinson/fisiopatología , Fenoxiacetatos/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Antiparkinsonianos/farmacología , Catalepsia/inducido químicamente , Citocromo P-450 CYP2D6/metabolismo , Inhibidores del Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Electrofisiología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Haloperidol/toxicidad , Humanos , Estructura Molecular , Fenoxiacetatos/química , Fenoxiacetatos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Proteínas de Unión al ADN/antagonistas & inhibidores , Pirimidinas/farmacología , Transactivadores/antagonistas & inhibidores , Línea Celular , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Diseño de Fármacos , Humanos , Cinética , Pirimidinas/síntesis química , Pirimidinas/química , Receptor de Adenosina A2A/metabolismo , Relación Estructura-Actividad , Regulador Transcripcional ERGRESUMEN
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Aminopiridinas/química , Química Farmacéutica/métodos , Pirimidinas/síntesis química , Diseño de Fármacos , Haloperidol/química , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Enfermedad de Parkinson/terapia , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Receptor de Adenosina A1/química , Receptor de Adenosina A2A/química , Solubilidad , Relación Estructura-ActividadRESUMEN
In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.
Asunto(s)
Acetamidas/uso terapéutico , Antagonistas del Receptor de Adenosina A2 , Pirimidinas/uso terapéutico , Acetamidas/síntesis química , Antagonistas del Receptor de Adenosina A1 , Animales , Conducta Animal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Sinergismo Farmacológico , Haloperidol , Humanos , Pirimidinas/síntesis química , Ratas , Rotación , Solubilidad , Relación Estructura-ActividadRESUMEN
4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Enfermedad de Parkinson/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Haloperidol , Humanos , Ligandos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The present article describes a selection of a new class of small molecule antagonists for the h-GnRH receptor, their preparation, and evaluation in vitro. Three computational methods were combined into a consensus score, to rank order virtual templates. The top 5% of templates were further evaluated in silico and assessed for novelty and synthetic accessibility. The tetrahydropyrido[4,3-d]pyrimidine-2,4-dione core was selected for synthesis and evaluated in vitro. Using an array approach for analog design and synthesis, we were able to drive the binding below 10nM for the h-GnRH receptor after two rounds of optimization.
Asunto(s)
Hidrógeno/química , Pirimidinas/química , Pirimidinas/farmacología , Receptores LHRH/antagonistas & inhibidores , Bases de Datos Factuales , Etilaminas/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Receptores LHRH/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.