Tricarbonylchromium complexes of Hantzsch esters possess robust calcium antagonist activity.
Tricarbonylchromium complexes of Hantzsch esters possess robust calcium antagonist activity.
复制标题
Hantzsch 酯的三羰基铬络合物具有强大的钙拮抗活性。
DOI：
10.1021/jm00084a023
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发表时间：
1992
影响因子：
7.3
通讯作者：
Kwon,YW
中科院分区：
文献类型：
--
作者：
Hubler,TL;Meikrantz,SB;Bitterwolf,TE;Natale,NR;Triggle,DJ;Kwon,YW
4-芳基-1，4-二氢吡啶(Hantzsch酯)是重要的心血管药物，具有钙通道拮抗剂活性。1对这类化合物的合成继续感兴趣，这既是为了阐明作用的分子基础，也是为了改善它们的药理学概况。2(芳烃)铬三甲基衍生物在合成3和最近作为药物受体结合的探针4的生物应用中得到了广泛的应用。将功能化药物用作任何药物-受体相互作用的探针的一个中心问题是，引入的结构变化是否扰乱了结合或取消了生物活性。5我们首次报道了三甲基铬4-芳基-1，4-二氢吡啶的合成，6并证明了(1)(A)Trigger，DJ；Langs，D.A.；Janis，RA钙通道配体：1，4-二氢吡啶的结构-功能关系。地中海医院。Rev.1989，9,123-180。(B)Janis，RA；Trigger，DJ。钙离子通道的新发展。J.Med.化学。1983年，26,775-785.(2)(A)Frigerio，M.；Zaliani，A.；Riva，C.；Palmisano，G.；Pilati，T.；Gandolfi，C.A.非同寻常的高立体比类Hantzsch环化反应：首次鉴定的2-氯亚甲基-L，2，3，4-四氢吡啶。四面体Lett。1988，29,6335-6338.(B)Davis，R.；Kern，Jr；Kurz，L.J.；Pfister，JR。J.Am化学。SoC。(C)Baldwin，JJ；Claemon，DA；Lumma，P.K.；McClure，DE；Rosenthal，S.A.；Winquist，RJ；Faison，EP；Kaczorowski，G.J.；Trumble，M.J.；Smith，G.M.Diethyl 3，6-二氢-2，4-二甲基-2，6-甲氨基-L，3-苯并噻唑-5，11-二羧酸盐作为钙通道拮抗剂：与Nitrendiine有关的构象受限的新的Hantzsch 1，4-二氢吡啶类似物作为受体位点构象的探针。J.Med.化学。(D)Arrowsmith，Je；Campbell，S.F.；Cross，PE；Stubbs，J.K.；Burges，RA；Gardiner，D.G.；Blackburn，K.J.长效二氢吡啶钙拮抗剂。1.含有碱性取代基的2-烷氧甲基衍生物。J.Med.化学。1986、29、1696-1702年。这些分子是强健而稳定的钙拮抗剂，它们与[~3H]-1，4-二氢吡啶结合在心肌细胞膜的钙通道上竞争。
4-Aryl-1, 4-dihydropyridines (Hantzsch esters) are im-portant cardiovascular drugs whichexhibit calcium chan-nel antagonist activity. 1 Interest in the synthesis of this class of compounds continues, both to elucidate the mo-lecular basis of action and to improve their pharmaco-logical profile. 2 (Arene) chromium tricarbonyl derivatives have found wide application in synthesis3 and, more re-cently, in biological applications4 as probes of drug-receptor binding. A central question for the potential use of a functionalized drug as a probe of any drug-receptor interaction is whether the structural change introduced perturbs the binding or abolishes biological activity. 5 We herein report the first preparation of tricarbonylchromium 4-aryl-1, 4-dihydropyridines, 6 and present evidence that (1)(a) Triggle, DJ; Langs, D. A.; Janis, RA Ca2+ Channel Ligands: Structure-Function Relationships of the 1, 4-Di-hydropyridines. Med. Res. Rev. 1989, 9,123-180.(b) Janis, RA; Triggle, DJ New Developments in Ca2+ Channel An-tagonists. J. Med. Chem. 1983, 26, 775-785.(2)(a) Frigerio, M.; Zaliani, A.; Riva, C.; Palmisano, G.; Pilati, T.; Gandolfi, C. A. Ca++-Modulators. UnusualHighly Stereospe-cific Hantzsch-like cyclization: First Authenticated Example of 2-chloromethylene-l, 2, 3, 4-tetrahydropyridine. Tetrahedron Lett. 1988, 29, 6335-6338.(b) Davis, R.; Kern, JR; Kurz, L. J.; Pfister, JR Enantioselective Synthesis of Dihydropyridine Sulfones. J. Am. Chem. Soc. 1988, 110, 7873-7874.(c) Baldwin, JJ; Claremon, DA; Lumma, P. K.; McClure, DE; Rosenthal, S. A.; Winquist, RJ; Faison, EP; Kaczorowski, G. J.; Trumble, M. J.; Smith, G. M. Diethyl 3, 6-Dihydro-2, 4-dimethyl-2, 6-methano-l, 3-benzothiazocine-5, ll-dicarboxylates as Calcium Entry Antagonists: New Conformationally Restrained Analogues of Hantzsch 1, 4-Dihydropyridines Related to Nitrendipine as Probes for Receptor-Site Conformation. J. Med. Chem. 1987, 30, 690-695.(d) Arrowsmith, JE; Campbell, S. F.; Cross, PE; Stubbs, J. K.; Burges, RA; Gardiner, D. G.; Blackburn, K. J. Long-Acting dihydropyridine Calcium Antagonists. 1. 2-Alkoxymethyl Derivatives Incorporating Basic Substituents. J. Med. Chem. 1986, 29, 1696-1702. these molecules are robust and stable calcium antagonists which compete with [3H]-1, 4-dihydropyridine binding at Ca2+ channels in cardiac membranes.