A novel series of indazole-/indole-based glucagon receptor antagonists

被引：12

作者：

Lin, Songnian ^{[1
]}

Zhang, Fengqi ^{[1
]}

Jiang, Guoqiang ^{[1
]}

Qureshi, Sajjad A. ^{[1
]}

Yang, Xiaodong ^{[1
]}

Chicchi, Gary G. ^{[1
]}

Tota, Laurie ^{[1
]}

Bansal, Alka ^{[1
]}

Brady, Edward ^{[1
]}

Trujillo, Maria ^{[1
]}

Salituro, Gino ^{[1
]}

Miller, Corey ^{[1
]}

Tata, James R. ^{[1
]}

Zhang, Bei B. ^{[1
]}

Parmee, Emma R. ^{[1
]}

机构：

[1] Merck Res Labs, Early Dev & Discovery Sci & Preclin Dev, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 19期

关键词：

Glucagon receptor antagonist; Indazole; Indole; Diabetes; Glucose lowering; HEPATIC GLUCOSE-PRODUCTION; THERAPEUTIC TARGET;

D O I：

10.1016/j.bmcl.2015.08.015

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole-and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10 mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：4143 / 4147

页数：5

共 50 条

[31] Discovery of novel indole-based aroylhydrazones as anticonvulsants: Pharmacophore-based design
Angelova, Violina T.
Rangelov, Miroslav
Todorova, Nadezhda
Dangalov, Miroslav
Andreeva-Gateva, Pavlina
Kondeva-Burdina, Magdalena
Karabeliov, Valentin
Shivachev, Boris
Tchekalarova, Jana
BIOORGANIC CHEMISTRY, 2019, 90
[32] Synthesis and in vitro Evaluation of Novel Indole-Based Sigma Receptors Ligands
Yarim, Mine
Koksal, Meric
Schepmann, Dirk
Wuensch, Bernard
CHEMICAL BIOLOGY & DRUG DESIGN, 2011, 78 (05) : 869 - 875
[33] Design, synthesis, and effects of novel phenylpyrimidines as glucagon receptor antagonists
Choi, Hojung
Lee, Chang-Yong
Park, Eun-Young
Lee, Kyoung Mee
Shin, Dongyun
Jun, Hee-Sook
BIOORGANIC & MEDICINAL CHEMISTRY, 2018, 26 (21) : 5701 - 5710
[34] Human glucagon receptor antagonists based on alkylidene hydrazides
Ling, A
Plewe, M
Gonzalez, J
Madsen, P
Sams, CK
Lau, J
Gregor, V
Murphy, D
Teston, K
Kuki, A
Shi, S
Truesdale, L
Kiel, D
May, J
Lakis, J
Anderes, K
Iatsimirskaia, E
Sidelmann, UG
Knudsen, LB
Brand, CL
Polinsky, A
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (04) : 663 - 666
[35] Discovery of selective indole-based prostaglandin D2 receptor antagonist
Iwahashi, Maki
Shimabukuro, Atsushi
Onoda, Takahiro
Matsunaga, Yoko
Okada, Yutaka
Matsumoto, Ryoji
Nambu, Fumio
Nakai, Hisao
Toda, Masaaki
BIOORGANIC & MEDICINAL CHEMISTRY, 2011, 19 (15) : 4574 - 4588
[36] The design and synthesis of a novel series of indole derived selective ETA antagonists
Rawson, DJ
Dack, KN
Dickinson, RP
James, K
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (02) : 125 - 128
[37] Novel indole-based inhibitors of IMPDH: Introduction of hydrogen bond acceptors at indole C-3
Watterson, SH
Dhar, TGM
Ballentine, SK
Shen, ZQ
Barrish, JC
Cheney, D
Fleener, CA
Rouleau, KA
Townsend, R
Hollenbaugh, DL
Iwanowicz, EJ
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (07) : 1273 - 1276
[38] Novel Indole-Based Analogs of Melatonin: Synthesis and in Vitro Antioxidant Activity Studies
Shirinzadeh, Hanif
Eren, Burcu
Gurer-Orhan, Hande
Suzen, Sibel
Ozden, Seckin
MOLECULES, 2010, 15 (04) : 2187 - 2202
[39] Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones
Cihan-Ustundag, Gokce
Gursoy, Elif
Naesens, Lieve
Ulusoy-Guzeldemirci, Nuray
Capan, Gultaze
BIOORGANIC & MEDICINAL CHEMISTRY, 2016, 24 (02) : 240 - 246
[40] Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD)
Lu, Jianyu
Chan, Chi-chung
Sun, Deheng
Hui, Guoping
He, Huijun
Li, Jian
Dong, Jiaqiang
Liu, Kai
Shen, Liang
Hu, Lihong
Gu, Qingyang
Chen, Shuhui
Wang, Tielin
Gong, Ting
Tang, Wei
Li, Xiaoting
Zhu, Xiaotong
Zeng, Xu
Zhu, Yingjie
Xia, Yuanfeng
Huang, Yuanyuan
Zhu, Yusong
Liu, Zhenteng
Ding, Charles Z.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2022, 66

← 1 2 3 4 5 →