Isoquinolone derivatives as lysophosphatidic acid receptor 5 (LPA5) antagonists: Investigation of structure-activity relationships, ADME properties and analgesic effects.

Blockade of lysophosphatidic acid receptor 5 (LPA5) by a recently reported antagonist AS2717638 (2) attenuated inflammatory and neuropathic pains, although it showed moderate in vivo efficacy and its structure-activity relationships and the ADME properties are little studied. We therefore designed and synthesized a series of isoquinolone derivatives and evaluated their potency in LPA5 calcium mobilization and cAMP assays. Our results show that substituted phenyl groups or bicyclic aromatic rings such as benzothiophenes or benzofurans are tolerated at the 2-position, 4-substituted piperidines are favored at the 4-position, and methoxy groups at the 6- and 7-positions are essential for activity. Compounds 65 and 66 showed comparable in vitro potency, excellent selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than 2 and had longer-lasting effects in an inflammatory pain model, and 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia at doses that had no effect on the locomotion in rats. These results suggest that these isoquinolone derivatives as LPA5 antagonists are of promise as potential analgesics. [Display omitted] • Structure-activity relationships at multiple positions of the isoquinolone were explored and a total of 63 isoquinolone derivatives were obtained. • A novel strategy using Chan-Lam coupling, conducted open to the air, was established to prepare 2-substituted isoquinolones with good yields and reproducibility. • Representative compounds (65 , 66) showed good potency and selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. • Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than previously reported AS2717638 and had longer-lasting effects in an inflammatory pain model. • 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia. [ABSTRACT FROM AUTHOR]