Isoquinoline Derivatives as Potent, Selective, and Orally Active CRTH2 Antagonists

: Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 antagonists bearing a methylene linker between the isoquinoline and benzamide moieties were described. Optimization focusing on the substituents of the benzamide portion in the right hand part of the molecule led to the identification of TASP0412098 (9l), which is a potent, selective CRTH2 antagonist (binding affinity: IC50=2.1 nM, functional activity: IC50=12 nM). Compound 9l, which was orally bioavailable in mice and guinea pigs, showed in vivo efficacy after oral administration in a bronchial asthma model of guinea pigs.