RESUMO
Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors and derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We also show screening results for three diverse protein targets. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.
Assuntos
Descoberta de Drogas , Bibliotecas de Moléculas Pequenas , Bibliotecas de Moléculas Pequenas/química , Descoberta de Drogas/métodos , Biblioteca Gênica , DNA/genética , DNA/químicaRESUMO
The epithelial Na+ channel (ENaC) is a key regulator of the volume of airway surface liquid (ASL) and is found in the human airway epithelium. In cystic fibrosis (CF), Na+ hyperabsorption through ENaC, in the absence of cystic fibrosis transmembrane conductance regulator mediated anion secretion, results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This review summarizes the published patent applications from 2014 to the end of 2016 that claim approaches to inhibit the function of ENaC for the treatment of CF.
Assuntos
Fibrose Cística , Regulador de Condutância Transmembrana em Fibrose Cística , Bloqueadores do Canal de Sódio Epitelial , Canais Epiteliais de Sódio , Humanos , Depuração MucociliarRESUMO
The epithelial Na(+) channel, ENaC, is a key regulator of the volume of airway surface liquid in the human airway epithelium. In cystic fibrosis (CF), Na(+) hyperabsorption through ENaC in the absence of CFTR-mediated anion secretion results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC-blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This article summarizes the published patent applications from 2010 that claim approaches to inhibit the function of ENaC for utility in the treatment of CF. Patents were located though SciFinder(®), using "ENaC" as the keyword from 2010 onwards; documents not relevant to CF were then manually removed.
Assuntos
Fibrose Cística/tratamento farmacológico , Bloqueadores do Canal de Sódio Epitelial/uso terapêutico , Canais Epiteliais de Sódio/metabolismo , Animais , Fibrose Cística/metabolismo , Diacilglicerol Quinase/antagonistas & inibidores , Indústria Farmacêutica , Humanos , Patentes como AssuntoRESUMO
A series of new N-type (Ca(v)2.2) calcium channel blockers derived from the 'hit' structures 2-(3-bromo-4-fluorophenyl)-3-(2-pyridin-2-ylethyl)thiazolidin-4-one 9 and its 2-[4-(4-bromophenyl)pyridin-3-yl]-3-isobutyl analogue 10 is described. Extensive SAR studies using a range of synthetic approaches resulted in novel, patented compounds with IC50 values of up to 0.2 microM in an in vitro IMR32 assay, and selectivities for N/L of up to 30-fold. The new compounds described have potential in treatment of neuropathic pain.
