ABSTRACT
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.
Subject(s)
Acrylamide/chemical synthesis , Acrylamide/chemistry , Amines/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacologyABSTRACT
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.
Subject(s)
Indazoles/chemistry , Nerve Tissue Proteins/antagonists & inhibitors , Transient Receptor Potential Channels/antagonists & inhibitors , Administration, Oral , Analgesics/chemistry , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Biological Availability , CHO Cells , Calcium Channels , Cricetulus , Freund's Adjuvant , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Mice, Inbred C57BL , Mustard Plant , Plant Oils , Rats, Wistar , Species Specificity , Structure-Activity Relationship , TRPA1 Cation Channel , TRPC Cation Channels/antagonists & inhibitorsABSTRACT
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.
