Grunewald Gary L, Seim Mitchell R, Regier Rachel C, Martin Jennifer L, Gee Christine L, Drinkwater Nyssa, Criscione Kevin R
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
J Med Chem. 2006 Sep 7;49(18):5424-33. doi: 10.1021/jm060466d.
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 microM) is the most potent compound in this series and is quite selective for PNMT versus the alpha2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 microM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.
3-氟甲基-7-(N-取代氨磺酰基)-1,2,3,4-四氢异喹啉（14、16以及18 - 22）是苯乙醇胺N-甲基转移酶（PNMT）的高效且选择性抑制剂。对3-氟甲基-7-(N-烷基氨磺酰基)-1,2,3,4-四氢异喹啉（如16）进行的分子模拟研究表明，磺酰胺基的-NH-可与Lys57的侧链形成氢键。然而，SAR研究以及对人PNMT（hPNMT）与7复合物的晶体结构分析表明，与酶形成有利相互作用的是磺酰胺基的氧原子，而非磺酰胺基的-NH-。因此，我们推测用亚甲基取代磺酰胺基的-NH-可能会得到对PNMT仍保持活性且亲脂性增加的化合物，从而增加其穿越血脑屏障的可能性。合成了一系列3-氟甲基-7-磺酰基-1,2,3,4-四氢异喹啉（23 - 30），并评估了它们对PNMT的抑制活性以及对α2-肾上腺素能受体的亲和力。将这些化合物与其等排磺酰胺（14、16以及18 - 22）进行比较，结果表明砜类化合物比其相应的磺酰胺类化合物亲脂性更强，但活性更低。砜24（hPNMT的Ki = 1.3 μM）是该系列中活性最强的化合物，对PNMT相对于α2-肾上腺素能受体具有相当高的选择性，但24的活性低于相应的磺酰胺16（hPNMT的Ki = 0.13 μM）。我们还报道了hPNMT与磺酰胺15复合物的晶体结构，从中确定了hPNMT活性位点内一个潜在的氢键受体，即Asn39的主链羰基氧。该残基与磺酰胺基的-NH-之间的相互作用可能是磺酰胺类化合物相对于砜类化合物抑制活性增强的主要原因。
