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1.
Bioorg Med Chem Lett ; 21(9): 2715-20, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21195614

RESUMO

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.


Assuntos
Azepinas/síntese química , Pirimidinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Animais , Azepinas/química , Azepinas/farmacologia , Azepinas/uso terapêutico , Modelos Animais de Doenças , Cães , Masculino , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Incontinência Urinária/tratamento farmacológico
2.
Toxicol Sci ; 159(1): 94-101, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28903488

RESUMO

There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non-rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safety margin between hERG IC50 and clinical peak free plasma exposure (0.80); safety margin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that from an early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase.


Assuntos
Doenças do Cão/fisiopatologia , Eletrocardiografia , Síndrome do QT Longo/veterinária , Animais , Cães , Humanos , Síndrome do QT Longo/fisiopatologia , Técnicas de Patch-Clamp , Curva ROC
3.
J Med Chem ; 57(12): 5258-69, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24878222

RESUMO

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.


Assuntos
Azepinas/química , Fármacos do Sistema Nervoso Central/química , Pirimidinas/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Animais , Azepinas/síntese química , Azepinas/farmacologia , Barreira Hematoencefálica/metabolismo , Células CHO , Fármacos do Sistema Nervoso Central/síntese química , Fármacos do Sistema Nervoso Central/farmacologia , Cricetulus , Cães , Desenho de Fármacos , Humanos , Células Madin Darby de Rim Canino , Permeabilidade , Pirimidinas/síntese química , Pirimidinas/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade , Incontinência Urinária por Estresse/tratamento farmacológico
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