Importance of the Aromatic Ring in Andrenergic Amines. 5. Nonaromatic Analogues of Phenylethanolamine as Inhibitors of Phenylethanolamine N-Methyltransferase: Role of Hydrophobic and Steric Interactions

Article abstract of DOI:10.1021/jm00133a003

The synthesis of five classes of nonaromatic analogues of β-phenylethanolamine and an evaluation of their inhibitory potency (IC50) for phenylethanolamine N-methyltransferase (PNMT) are described.The key intermediates for the synthesis of the ethanolamines were the appropriate aldehydes or ketones.The aldehydes 11a (cyclobutyl) and 13a (cycloheptyl) of type A were prepared from the correspondingacids by reduction of the acid to the alcohol with lithium aluminum hydride and oxidation of the alcohol to the aldehyde with pyridinium chlorochromate (PCC).The aldehydes 15a (cycloundecyl) and 41a (adamantyl) of type A were prepared by oxidation of the corresponding alcohols with PCC.The first reported synthesis of cyclononanecarboxaldehyde (type A, 14a) is described.This aldehyde was prepared via a multistep route beginning with a Favorskii rearrangement of 2-bromocyclodecanone to cyclononanecarboxylic acid.The acid was reduced with lithium aluminum hydride to the corresponding alcohol, which was subsequently oxidized to the aldehyde with PCC.The aldehydes or ketones were converted (with trimethylsilyl cyanide) into their cyanohydrin ethers, which were subsequently reduced to the desired ethanolamine with lithium aluminum hydride.The ethanolamines were tested as inhibitors (LCEC assay) of PNMT.The most potent inhibitors were the type A compounds 8 (cyclooctyl), 13c (cycloheptyl), 14c (cyclononyl), and 15c (cycloundecyl) and the type D compounds 26c (cyclononyl) and 27c (cycloundecyl) with IC50 values from 6 to 17 μM.It isconcluded that the binding site of PNMT accepts hydrophobic groups of an optimal length (ca. 6.4 Angstroem) and width (ca. 2.5 Angstroem) and has a significant height restriction for the hydrophobic group.The ethanolamine side chain prefers to lie away from and in the longitudinal axis of the hydrophobic group.An ethanolamine side chain attached to a cycloalkyl ring of n carbon atoms (types A and D) is almost always considerably more potent at inhibiting PNMT than the open-chain compounds of n total carbon atoms (types B, C, and E).