Copper-Catalyzed Three-Component Aminofluorination of Alkenes and 1,3-Dienes: Direct Entry to Diverse ß-Fluoroalkylamines.

Rapid and efficient access to structurally diverse ß-fluoroalkylamines is in high demand, with their wide presence and great importance in medicinal chemistry and drug development. Direct 1,2-aminofluorination of alkenes offers an ideal strategy for one-step entry to ß-fluorinated amines from readily available starting materials. Yet the synthesis of valuable ß-fluorinated alkylamines remains an unsolved challenge, due to the inherent incompatibility between electrophilic fluoride sources and the electron-rich alkylamines. We report an unprecedented, catalytic, three-component aminofluorination of diverse alkenes and 1,3-dienes, which has been achieved by an innovative copper-catalyzed electrophilic amination strategy using O-benzoylhydroxylamines as alkylamine precursors. The use of Et3N·3HF is also critical, not only as a commercially available and inexpensive fluoride source to enable effective fluorination but also as an acid source for the formation of aminyl radical cations for electrophilic amination. Mechanistic experiments suggest the involvement of aminyl radical species and carbon-radical intermediates under reaction conditions. This method features high regioselectivity and good tolerance of diverse functional groups and provides a practical and direct entry to a broad range of ß-fluorinated electron-rich alkylamines. Synthetic applications of this method have also been highlighted by its use for the rapid entry to ß-fluoridated amine-containing pharmaceuticals, natural products, and bioactive compounds.

High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators.

We previously identified phenylquinoxalinone CFTRact-J027 (4) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC50 of ∼200 nM and demonstrated its therapeutic efficacy in mouse models of constipation. Here, structure-activity studies were done on 36 synthesized phenylquinoxalinone analogs to identify compounds with improved potency and altered metabolic stability. Synthesis of the phenylquinoxalinone core was generally accomplished by condensation of 1,2-phenylenediamines with substituted phenyloxoacetates. Structure-activity studies established, among other features, the privileged nature of a properly positioned nitro moiety on the 3-aryl group. Synthesized analogs showed improved CFTR activation potency compared to 4 with EC50 down to 21 nM and with greater metabolic stability. CFTR activators have potential therapeutic indications in constipation, dry eye, cholestatic liver diseases, and inflammatory lung disorders.

Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation.

Constipation is a common condition for which current treatments can have limited efficacy. By high-throughput screening, we recently identified a phenylquinoxalinone activator of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel that stimulated intestinal fluid secretion and normalized stool output in a mouse model of opioid-induced constipation. Here, we report phenylquinoxalinone structure-activity analysis, mechanism of action, animal efficacy data in acute and chronic models of constipation, and functional data in ex vivo primary cultured human enterocytes. Structure-activity analysis was done on 175 phenylquinoxalinone analogs, including 15 synthesized compounds. The most potent compound, CFTRact-J027, activated CFTR with EC50 ∼ 200 nM, with patch-clamp analysis showing a linear CFTR current-voltage relationship with direct CFTR activation. CFTRact-J027 corrected reduced stool output and hydration in a mouse model of acute constipation produced by scopolamine and in a chronically constipated mouse strain (C3H/HeJ). Direct comparison with the approved prosecretory drugs lubiprostone and linaclotide showed substantially greater intestinal fluid secretion with CFTRact-J027, as well as greater efficacy in a constipation model. As evidence to support efficacy in human constipation, CFTRact-J027 increased transepithelial fluid transport in enteroids generated from normal human small intestine. Also, CFTRact-J027 was rapidly metabolized in vitro in human hepatic microsomes, suggesting minimal systemic exposure upon oral administration. These data establish structure-activity and mechanistic data for phenylquinoxalinone CFTR activators, and support their potential efficacy in human constipation.