RESUMEN
New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
Asunto(s)
Azepinas/síntesis química , Pirimidinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Animales , Azepinas/química , Azepinas/farmacología , Azepinas/uso terapéutico , Modelos Animales de Enfermedad , Perros , Masculino , Estructura Molecular , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Incontinencia Urinaria/tratamiento farmacológicoRESUMEN
A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.
Asunto(s)
Bencilaminas/química , Química Farmacéutica/métodos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Conformación Molecular , Receptores de Serotonina/metabolismo , Serotonina/química , Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.
Asunto(s)
Bencilaminas/síntesis química , Bencilaminas/farmacología , Éteres Fenílicos/síntesis química , Éteres Fenílicos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Bencilaminas/química , Técnicas Químicas Combinatorias , Humanos , Estructura Molecular , Éteres Fenílicos/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A branching synthetic strategy was used to efficiently generate structurally diverse scaffolds, which span a broad area of chemical descriptor space, and their biological activity against MRSA was demonstrated.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Resistencia a la Meticilina , Staphylococcus aureus/efectos de los fármacosRESUMEN
A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.
RESUMEN
The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.
RESUMEN
The synthesis of the C-1-C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1-C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key beta-keto-dithiane unit required for the synthesis of the AB spiroketal fragment. [reaction: see text]
RESUMEN
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
Asunto(s)
Azepinas/química , Fármacos del Sistema Nervioso Central/química , Pirimidinas/química , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/química , Animales , Azepinas/síntesis química , Azepinas/farmacología , Barrera Hematoencefálica/metabolismo , Células CHO , Fármacos del Sistema Nervioso Central/síntesis química , Fármacos del Sistema Nervioso Central/farmacología , Cricetulus , Perros , Diseño de Fármacos , Humanos , Células de Riñón Canino Madin Darby , Permeabilidad , Pirimidinas/síntesis química , Pirimidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Relación Estructura-Actividad , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológicoRESUMEN
A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies.
Asunto(s)
Diseño de Fármacos , Naftalenos/química , Naftalenos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Animales , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Células CACO-2 , Humanos , Estructura Molecular , Naftalenos/síntesis química , Ratas , Flujo Sanguíneo Regional , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por Sustrato , Factores de TiempoRESUMEN
A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.