| Abstrakt: |
(±)-7-Aminosulfonyl-3-fluoromethyl-1,2,3,4-tetrahydroisoquinoline (7) is one of the most potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) reported to date, but a blood−brain barrier (BBB) model indicates that it cannot penetrate the BBB. To increase the lipophilicity of 7 by addition of a nonpolar substituent to the sulfonamide nitrogen, a small library of (±)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines was synthesized and evaluated as inhibitors of PNMT and for affinity at the α2-adrenoceptor. In addition, this library probed the PNMT active site surrounding the sulfonamide nitrogen of 7. Bulky substituents on the sulfonamide nitrogen are disfavored at the PNMT active site more so than at the α2-adrenoceptor (thus reducing selectivity). On the other hand, alkyl chains on the sulfonamide nitrogen that contain an electron dense atom, such as a fluorine, are favored in the PNMT active site and possess little α2-adrenoceptor affinity, thereby conferring good selectivity (>500). Several members of the library (8, 14, 17, and 18) have excellent PNMT inhibitory potency and selectivity and are predicted, on the basis of their ClogP value (>0.5), to penetrate the BBB to a significant extent. Compounds 17 and 18 are the most potent and selective PNMT inhibitors reported to date. |
