RESUMEN
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
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
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 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
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]