RESUMEN
APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
RESUMEN
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
A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.
Asunto(s)
Química Farmacéutica/métodos , Citocromo P-450 CYP3A/química , Iones , Receptores LHRH/antagonistas & inhibidores , Uracilo/análogos & derivados , Diseño de Fármacos , Hormona Liberadora de Gonadotropina/química , Humanos , Cinética , Modelos Químicos , Estructura Molecular , Péptidos/química , Estereoisomerismo , Relación Estructura-Actividad , Uracilo/químicaRESUMEN
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
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
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.