Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor

被引：7
|
作者：
Fjellaksel, Richard [1 ,2 ,3 ]
Boomgaren, Marc [3 ]
Sundset, Rune [1 ,4 ]
Haraldsen, Ira H. [5 ]
Hansen, Jorn H. [3 ]
Riss, Patrick J. [5 ,6 ,7 ]
机构：
[1] UiT Arctic Univ Norway, Dept Clin Med, Med Imaging Grp, N-9037 Tromso, Norway
[2] UiT Arctic Univ Norway, Dept Pharm, Drug Transport & Delivery Grp, N-9037 Tromso, Norway
[3] UiT Arctic Univ Norway, Dept Chem, Organ Chem Grp, N-9037 Tromso, Norway
[4] UNN Univ Hosp North Norway, Div Diagnost, PET Imaging Ctr, N-9038 Tromso, Norway
[5] Oslo Univ Hosp, Dept Neuropsychiatry & Psychosomat Med, Oslo, Norway
[6] Univ Oslo, Dept Chem, Real SFI, POB 1033, N-0371 Oslo, Norway
[7] Norsk Med Syklotronsenter AS, Postboks 4950 Nydalen, N-0424 Oslo, Norway
来源：
MEDCHEMCOMM | 2017年 / 8卷 / 10期
关键词：
TESTOSTERONE; PHARMACOKINETICS; RATIONALE; CHEMISTRY; DISCOVERY; AGONISTS; INSIGHT; POTENT;
D O I：
10.1039/c7md00320j
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4piperazinyl- benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition. Our main purpose was to find a more soluble compound based on the WAY207024 lead with nanomolar potency to inhibit the GnRH receptor. A late stage diversification by the use of click chemistry was, furthermore developed to allow for expansion of the library in future optimisations. All compounds were tested in a functional assay to determine the individual potency of inhibiting stimulation of the receptor by the endogenous agonist GnRH. In conclusion, we found that compound 8a showed improved solubility compared to WAY207024 and nanomolar affinity to GnRH receptor.
引用
收藏
页码：1965 / 1969
页数：5
相关论文
共 50 条
  • [1] Small molecule antagonists of the gonadotropin-releasing hormone (GnRH) receptor: Structure-activity relationships of small heterocyclic groups appended to the 2-phenyl-4-piperazinyl-benzimidazole template
    Hauze, Diane B.
    Chengalvala, Murty V.
    Cottom, Joshua E.
    Feingold, Irene B.
    Garrick, Lloyd
    Green, Daniel M.
    Huselton, Christine
    Kao, Wenling
    Kees, Kenneth
    Lundquist, Joseph T.
    Mann, Charles W.
    Mehlmann, John F.
    Rogers, John F.
    Shanno, Linda
    Wrobel, Jay
    Pelletier, Jeffrey C.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (07) : 1986 - 1990
  • [2] Structure activity relationships of the linker group in 2-phenyl-4-piperazinyl-benzimidazole antagonists of the Gonadotropin-Releasing Hormone Receptor (GnRH)
    Hauze, Diane B.
    Pelletier, Jeffrey C.
    Mann, Charles W.
    Green, Daniel
    Rogers, John
    Chengalvala, Murty V.
    Cottom, Joshua E.
    Shanno, Linda
    Feingold, Irene B.
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2006, 231
  • [3] Synthesis and biological evaluation of piperazinyl heterocyclic antagonists of the gonadotropin releasing hormone (GnRH) receptor
    Vera, Matthew D.
    Lundquist, Joseph T.
    Chengalvala, Murty V.
    Cottom, Joshua E.
    Feingold, Irene B.
    Garrick, Lloyd M.
    Green, Daniel M.
    Hauze, Diane B.
    Mann, Charles W.
    Mehlmann, John F.
    Rogers, John F.
    Shanno, Linda
    Wrobel, Jay E.
    Pelletier, Jeffrey C.
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (08) : 2512 - 2515
  • [4] Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)
    Yang, Xin
    Lin, Guifeng
    Xia, Anjie
    Liu, Jingming
    Zhang, Shiyu
    Zhou, Pei
    Wang, Yiwei
    Zhang, Jiahao
    Zhou, Yangli
    Chen, Pei
    Wang, Yifei
    Zheng, Tao
    Li, Linli
    Yang, Shengyong
    JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2022, 62 (20) : 5009 - 5022
  • [5] Discovery of a novel, orally active, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist
    Li, Haitao
    Anderes, Kenna L.
    Kraynov, Eugenia A.
    Luthin, David R.
    Do, Quyen-Quyen
    Hong, Yufeng
    Tompkins, Eileen
    Sun, Eric T.
    Rajapakse, Ranjan
    Pathak, Ved P.
    Christie, Lance C.
    Vazir, Haresh
    Castillo, Rosemary
    Gregory, Margaret L.
    Castro, Mary
    Nared-Hood, Karen
    Paderes, Genevieve
    Anderson, Mark B.
    JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (11) : 3362 - 3367
  • [6] Gonadotropin-Releasing Hormone (GnRH) Receptor Structure and GnRH Binding
    Flanagan, Colleen A.
    Manilall, Ashmeetha
    FRONTIERS IN ENDOCRINOLOGY, 2017, 8
  • [7] The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists
    Luthin, DR
    Hong, YF
    Pathak, VP
    Paderes, G
    Nared-Hood, KD
    Castro, MA
    Vazir, H
    Li, HT
    Tompkins, E
    Christie, L
    May, JM
    Anderson, MB
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (23) : 3467 - 3470
  • [8] Synthesis of orally active small-molecule gonadotropin-releasing hormone antagonists
    Tucci, FC
    Chen, C
    CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT, 2004, 7 (06) : 832 - 847
  • [9] Internalization kinetics of the gonadotropin-releasing hormone (GnRH) receptor
    Vrecl, M
    Heding, A
    Hanyaloglu, A
    Taylor, PL
    Eidne, KA
    PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2000, 439 (03): : R19 - R20
  • [10] Internalization kinetics of the gonadotropin-releasing hormone (GnRH) receptor
    Milka Vrecl
    Anders Heding
    Aylin Hanyaloglu
    Philip L. Taylor
    Karin A. Eidne
    Pflügers Archiv, 2000, 439 : r019 - r020
12345