RESUMO
Bridgehead metallation is possible in a ketone having the welwistatin skeleton, and this facilitates installation of the isothiocyanate function present in the natural product, and also enables synthesis of remarkable bridgehead alkenes.
Assuntos
Alcaloides/química , Alcenos/química , Modelos Moleculares , Cristalografia por Raios X , Alcaloides Indólicos , Estrutura Molecular , Compostos de Selênio/química , Óxidos de SelênioRESUMO
A kinetic template-guided tethering (KTGT) strategy has been developed for the site-directed discovery of fragments that bind to defined protein surfaces, where acrylamide-modified fragments can be irreversibly captured in a protein-templated conjugate addition reaction. Herein, an efficient and facile method is reported for the preparation of acrylamide libraries from a diverse range of amine fragments using a solid-supported quaternary amine base.
Assuntos
Acrilamida/síntese química , Acrilamida/química , Aminas/química , Catálise , Técnicas de Química Combinatória , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologiaRESUMO
A high throughput screening campaign identified 5-(2-chlorophenyl)indazole compound 4 as an antagonist of the transient receptor potential A1 (TRPA1) ion channel with IC50 = 1.23 µM. Hit to lead medicinal chemistry optimization established the SAR around the indazole ring system, demonstrating that a trifluoromethyl group at the 2-position of the phenyl ring in combination with various substituents at the 6-position of the indazole ring greatly contributed to improvements in vitro activity. Further lead optimization resulted in the identification of compound 31, a potent and selective antagonist of TRPA1 in vitro (IC50 = 0.015 µM), which has moderate oral bioavailability in rodents and demonstrates robust activity in vivo in several rodent models of inflammatory pain.