Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 240-256 |
| Number of pages | 17 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 141 |
| DOIs | |
| Publication status | Published - 2017 Sep 21 |
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Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity. / Kim, Taehun; Son, Woo Seung; Morshed, Mohammad Neaz; Londhe, Ashwini M.; Jung, Seo Yun; Park, Jong Hyun; Park, Woo Kyu; Lim, Sang Min; Park, Ki Duk; Cho, Sung Jin; Jeong, Kyu-Sung; Lee, Jiyoun; Pae, Ae Nim.
In: European Journal of Medicinal Chemistry, Vol. 141, 21.09.2017, p. 240-256.Research output: Contribution to journal › Article
TY - JOUR
T1 - Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against Ab-induced neurotoxicity
AU - Kim, Taehun
AU - Son, Woo Seung
AU - Morshed, Mohammad Neaz
AU - Londhe, Ashwini M.
AU - Jung, Seo Yun
AU - Park, Jong Hyun
AU - Park, Woo Kyu
AU - Lim, Sang Min
AU - Park, Ki Duk
AU - Cho, Sung Jin
AU - Jeong, Kyu-Sung
AU - Lee, Jiyoun
AU - Pae, Ae Nim
PY - 2017/9/21
Y1 - 2017/9/21
N2 - Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[20,3’:4,5]pyrrolo[1,2-d] [1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Abinduced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.
AB - Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[20,3’:4,5]pyrrolo[1,2-d] [1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Abinduced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD.
U2 - 10.1016/j.ejmech.2017.09.033
DO - 10.1016/j.ejmech.2017.09.033
M3 - Article
VL - 141
SP - 240
EP - 256
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -