Novel Imidazol-1-ylmethyl Substituted 1,2,5,6-Tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones as Potent and Selective CYP11B1 Inhibitors for the Treatment of Cushing's Syndrome

被引：64
作者：
Yin, Lina [1 ,2 ,3 ]
Lucas, Simon [1 ,2 ]
Maurer, Frauke [4 ]
Kazmaier, Uli [4 ]
Hu, Qingzhong [1 ,2 ]
Hartmann, Rolf W. [1 ,2 ]
机构：
[1] Univ Saarland, D-66123 Saarbrucken, Germany
[2] Helmholtz Inst Pharmaceut Res Saarland HIPS, D-66123 Saarbrucken, Germany
[3] Elexopharm GmbH, D-66123 Saarbrucken, Germany
[4] Univ Saarland, Inst Organ Chem, D-66123 Saarbrucken, Germany
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 14期
关键词：
HUMAN 17-ALPHA-HYDROXYLASE-17,20-LYASE CYP17; ALDOSTERONE SYNTHASE INHIBITORS; BIOLOGICAL EVALUATION; DERIVATIVES; DISEASES; THERAPY; BIARYLS; ENZYME; SERIES;
D O I：
10.1021/jm3003872
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC50 = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.
引用
收藏
页码：6629 / 6633
页数：5
相关论文
共 27 条
  • [1] Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
    Abadi, Ashraf H.
    Abou-Seri, Sahar M.
    Hu, Qingzhong
    Negri, Matthias
    Hartmann, Rolf W.
    [J]. MEDCHEMCOMM, 2012, 3 (06) : 663 - 666
  • [2] Design and synthesis of 1,3,5-trisubstituted 1,2,4-triazoles as CYP enzyme inhibitors
    Al-Soud, Yaseen A.
    Heydel, Michael
    Hartmann, Rolf W.
    [J]. TETRAHEDRON LETTERS, 2011, 52 (48) : 6372 - 6375
  • [3] Pharmacological therapy of Cushing's syndrome:: Drugs and indications
    Diez, Juan J.
    Iglesias, Pedro
    [J]. MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2007, 7 (05) : 467 - 480
  • [4] Imidazolylmethylbenzophenones as highly potent aromatase Inhibitors
    Gobbi, Silvia
    Cavalli, Andrea
    Negri, Matthias
    Schewe, Katarzyna E.
    Belluti, Federica
    Piazzi, Lorna
    Hartmann, Rolf W.
    Recanatini, Maurizio
    Bisi, Alessandra
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (15) : 3420 - 3422
  • [5] Lead optimization providing a series of flavone derivatives as potent nonsteroidal inhibitors of the cytochrome P450 aromatase enzyme
    Gobbi, Silvia
    Cavalli, Andrea
    Rampa, Angela
    Belluti, Federica
    Piazzi, Lorna
    Paluszcak, Anja
    Hartmann, Rolf W.
    Recanatini, Maurizio
    Bisi, Alessandra
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (15) : 4777 - 4780
  • [6] Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors:: Influence of heteroaryl derivatization on potency and selectivity
    Heim, Ralf
    Lucas, Simon
    Grombein, Cornelia M.
    Ries, Christina
    Schewe, Katarzyna E.
    Negri, Matthias
    Mueller-Vieira, Ursula
    Birk, Barbara
    Hartmannt, Rolf W.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (16) : 5064 - 5074
  • [7] First Selective CYP11B1 Inhibitors for the Treatment of Cortisol-Dependent Diseases
    Hille, Ulrike E.
    Zimmer, Christina
    Vock, Carsten A.
    Hartmann, Rolf W.
    [J]. ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (01): : 2 - 6
  • [8] Steroidogenic cytochrome P450 (CYP) enzymes as drug targets: Combining substructures of known CYP inhibitors leads to compounds with different inhibitory profile
    Hille, Ulrike E.
    Hu, Qingzhong
    Mendieta, Mariano A. E. Pinto-Bazurco
    Bartels, Marc
    Vock, Carsten A.
    Lauterbach, Thomas
    Hartmann, Rolf W.
    [J]. COMPTES RENDUS CHIMIE, 2009, 12 (10-11) : 1117 - 1126
  • [9] Novel CYP17 inhibitors: Synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls
    Hille, Ulrike E.
    Hu, Qingzhong
    Vock, Carsten
    Negri, Matthias
    Bartels, Marc
    Mueller-Vieira, Ursula
    Lauterbach, Thomas
    Hartmann, Rolf W.
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2009, 44 (07) : 2765 - 2775
  • [10] Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17) -: Part II:: Core rigidification and influence of substituents at the methylene bridge
    Hu, Qingzhong
    Negri, Matthias
    Jahn-Hoffmann, Kerstin
    Zhuang, Yan
    Olgen, Sureyya
    Bartels, Marc
    Mueller-Vieira, Ursula
    Lauterbach, Thomas
    Hartmann, Rolf W.
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2008, 16 (16) : 7715 - 7727
123