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Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354.
TLDR
Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM).
Discovery and Characterization of 2‐(Cyclopropanesulfonamido)‐N‐(2‐ethoxyphenyl)benzamide, ML382: a Potent and Selective Positive Allosteric Modulator of MrgX1
TLDR
An iterative parallel synthesis effort and a structure–activity relationship study of a series of arylsulfonamides led to the discovery of the first PAM of MrgX1, ML382.
Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.
TLDR
This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator based on multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GirK 1/2 and GIRk1/4.
Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and
TLDR
A series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3.5-Molecule, maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against γ-thrombin.
Discovery of potent and selective GIRK1/2 modulators via 'molecular switches' within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas.
TLDR
Novel 'molecular switches' that modulated the mode of pharmacology from inhibitor to activator was discovered on both the 3-cyclopropyl and N-phenyl moiety of the pyrazole core, providing the first highly selective GIRK1/2 activator.
Scheme 1, Chemical characterization of Probe ML382
Scheme 2, Preparation of Probe ML382