We synthesized a series of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs), aiming to improve the metabolic stability of the previously identified hit compound IPPAM-3 (2). Our results indicated that the 3-position of the 2-substituted phenyl ring in this series of IPPAM-3 derivatives is a hot spot for metabolism catalyzed by human hepatic microsomes. This conclusion was confirmed by the finding that 8, in which the 3-position is blocked by a fluorine substituent, exhibited superior metabolic stability (t1/2 21min versus 7min for parent compound 2). The primary route of metabolism of 8 was found to be oxidative defluorination, i.e., ipso-substitution of the fluorine atom to a hydroxyl group, affording catechol derivative 12. The primary metabolite 12 underwent further hydroxylation mainly on the 1,2,3,4-tetrahydroisoquinoline moiety. These findings should be helpful for design of IPPAMs with longer duration of action.