RESUMEN
A novel parallel medicinal chemistry (PMC)-enabled synthesis of 1H-pyrazolo[3,4-d]pyrimidines employing condensation of easily accessible N-pyrazolylamides and nitriles has been developed. The presented studies describe singleton and library enablements that allowed rapid generation of molecular diversity to examine C4 and C6 vectors. This chemistry enabled access to challenging alkyl substituents, expanding the overall chemical space beyond that available via typical C(sp2)-C(sp2) coupling and SNAr transformations. Furthermore, monomer group interconversions allowing the use of larger and more diverse amides and carboxylic acids as precursors to nitriles are discussed.
Asunto(s)
Amidas/química , Nitrilos/química , Pirazoles/química , Pirimidinas/química , Química Farmacéutica , Portadores de Fármacos , Humanos , Tamaño de la Partícula , Pirazoles/síntesis química , Pirimidinas/síntesis química , Propiedades de SuperficieRESUMEN
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Receptor del Glutamato Metabotropico 5/metabolismo , Animales , Femenino , Células HEK293 , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Masculino , Simulación del Acoplamiento Molecular , Piridinas/efectos adversos , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Amidas/química , Amidas/farmacología , Indoles/química , Indoles/farmacología , Receptor Muscarínico M1/metabolismo , Amidas/farmacocinética , Animales , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Indoles/farmacocinética , Ratones , Simulación del Acoplamiento Molecular , Receptor Muscarínico M1/agonistasRESUMEN
A sulfur-functionalized aminoacrolein derivative is used for the efficient and selective synthesis of heterocyclic sulfonyl chlorides, sulfonyl fluorides, and sulfonamides. The development of a 3-step parallel medicinal chemistry (PMC) protocol for the synthesis of pyrazole-4-sulfonamides effectively demonstrates the utility of this reagent. This reactivity was expanded to provide rapid access to other heterocyclic sulfonyl fluorides, including pyrimidines and pyridines, whose corresponding sulfonyl chlorides lack suitable chemical stability.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Ácidos Sulfínicos/síntesis química , Sulfonamidas/síntesis química , Química Farmacéutica , Técnicas Químicas Combinatorias , Compuestos Heterocíclicos/química , Estructura Molecular , Ácidos Sulfínicos/química , Sulfonamidas/químicaRESUMEN
Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.
Asunto(s)
Descubrimiento de Drogas , Epilepsia/tratamiento farmacológico , Activación del Canal Iónico/efectos de los fármacos , Canal de Potasio KCNQ2/metabolismo , Piperidinas/farmacología , Pirimidinas/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Electrochoque , Humanos , Canal de Potasio KCNQ2/agonistas , Microsomas/efectos de los fármacos , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.
Asunto(s)
Pirazinas/síntesis química , Pirazoles/síntesis química , Receptor del Glutamato Metabotropico 5/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Administración Oral , Regulación Alostérica , Animales , Antiparkinsonianos/efectos adversos , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Perros , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Células HEK293 , Humanos , Hipersensibilidad Tardía/inducido químicamente , Levodopa/efectos adversos , Macaca fascicularis , Células de Riñón Canino Madin Darby , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/fisiopatología , Pirazinas/farmacología , Pirazinas/toxicidad , Pirazoles/farmacología , Pirazoles/toxicidad , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.
Asunto(s)
Antipsicóticos/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/metabolismo , Esquizofrenia/tratamiento farmacológico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Sitios de Unión , Barrera Hematoencefálica/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cristalografía por Rayos X , GMP Cíclico/metabolismo , Bases de Datos Factuales , Diseño de Fármacos , Humanos , Técnicas In Vitro , Ratones , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Permeabilidad , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/genética , Conformación Proteica , Relación Estructura-ActividadRESUMEN
By use of chemical enablement and prospective design, a novel series of selective, brain penetrant PDE9A inhibitors have been identified that are capable of producing in vivo elevations of brain cGMP.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Encéfalo/enzimología , 3',5'-AMP Cíclico Fosfodiesterasas/química , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Animales , Encéfalo/metabolismo , GMP Cíclico/metabolismo , Humanos , Enlace de Hidrógeno , Ratones , Modelos Moleculares , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/farmacologíaRESUMEN
Using a combination of parallel and directed synthesis, the discovery of a highly potent and selective series of adenosine A3 agonists was achieved. High aqueous solubility, required for the intended parenteral route of administration, was achieved by the presence of one or two basic amine functional groups.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Adenosina/síntesis química , Adenosina/farmacología , Adenosina/análogos & derivados , Humanos , Conformación Molecular , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Agua/químicaRESUMEN
Selective adenosine A(3) agonists have potential utility for the prevention of perioperative myocardial ischemic injury. Herein, we report on the discovery and synthesis of compound 7. This amino nucleoside agonist possesses unprecedented levels of selectivity for the human adenosine A(3) receptor.