Inhibitors of phenylethanolamine N-methyltransferase that are predicted to penetrate the blood-brain barrier: design, synthesis, and evaluation of 3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines that possess low affinity toward the alpha2-adrenoceptor.
(+/-)-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 alpha2-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 alpha2-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 alpha2-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.
Romero
F Anthony
FA
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
Vodonick
Steven M
SM
Criscione
Kevin R
KR
McLeish
Michael J
MJ
Grunewald
Gary L
GL
D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008958:Models, Molecular; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D044005:Tetrahydroisoquinolines; D010625:Phenylethanolamine N-Methyltransferase