ABSTRACT
A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific. Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity.
Subject(s)
Carboxylic Acids/chemical synthesis , Chemistry, Pharmaceutical/methods , Hedgehog Proteins/agonists , Administration, Oral , Animals , Carboxylic Acids/pharmacology , Cell Line , Drug Design , Hedgehog Proteins/metabolism , Humans , Mice , Models, Biological , Models, Chemical , Stroke/drug therapy , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
A small family of phenyl quinazolinone ureas is reported as potent modulators of Hedgehog protein function. Preliminary SAR studies of the urea substituent led to a nanomolar Hedgehog antagonist.
Subject(s)
Hedgehog Proteins/antagonists & inhibitors , Quinazolinones/chemical synthesis , Animals , Cell Line , Hedgehog Proteins/physiology , Mice , Quinazolinones/chemistry , Quinazolinones/pharmacology , Signal Transduction , Structure-Activity RelationshipABSTRACT
Prostaglandin D2 (PGD2) acting at the CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells) has been linked with a variety of allergic and other inflammatory diseases. We describe a family of indole-1-sulfonyl-3-acetic acids that are potent and selective CRTH2 antagonists that possess good oral bioavailability. The compounds may serve as novel starting points for the development of treatments of inflammatory disease such as asthma, allergic rhinitis, and atopic dermatitis.
