Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a] pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition

被引：11

作者：

Akiu, Mayuko ^{[1
]}

Tsuji, Takashi ^{[1
]}

Sogawa, Yoshitaka ^{[1
]}

Terayama, Koji ^{[1
]}

Yokoyama, Mika ^{[1
]}

Tanaka, Jun ^{[1
]}

Asano, Daigo ^{[1
]}

Sakurai, Ken ^{[1
]}

Sergienko, Eduard ^{[2
]}

Sessions, E. Hampton ^{[2
]}

Gardell, Stephen J. ^{[3
]}

Pinkerton, Anthony B. ^{[2
]}

Nakamura, Tsuyoshi ^{[1
]}

机构：

[1] Daiichi Sankyo Co Ltd, R&D Div, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1408710, Japan

[2] Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA

[3] AdventHealth, Translat Res Inst, Orlando, FL 32804 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 43卷

关键词：

NAMPT activators; NAD plus; Triazolopyridines; CYP inhibition; LogD; NAD BIOSYNTHESIS; MITOCHONDRIAL; METABOLISM; MONONUCLEOTIDE; SIRTUINS; RIBOSIDE; STATE;

D O I：

10.1016/j.bmcl.2021.128048

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD+ salvage pathway. Since NAD+ plays a pivotal role in many biological processes including metabolism and aging, activation of NAMPT is an attractive therapeutic target for treatment of diverse array of diseases. Herein, we report the continued optimization of novel urea-containing derivatives which were identified as potent NAMPT activators. Early optimization of HTS hits afforded compound 12, with a triazolopyridine core, as a lead compound. CYP direct inhibition (DI) was identified as an issue of concern, and was resolved through modulation of lipophilicity to culminate in 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea (21), which showed potent NAMPT activity accompanied with attenuated CYP DI towards multiple CYP isoforms.

引用

页数：7

共 50 条

[21] 1-(2,3,4,5,6-Pentamethylbenzyl)-2-(pyridin-2-yl)-1H-benzimidazole
Angay, Firat
Celik, Omer
Barlik, Orhan
Ulusoy, Mahmut
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2014, 70 : O563 - +
[22] Discovery of N-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of TGF-β Type I Receptor Kinase as Cancer Immunotherapeutic/Antifibrotic Agent
Jin, Cheng Hua
Krishnaiah, Maddeboina
Sreenu, Domalapally
Subrahmanyam, Vura B.
Rao, Kota S.
Lee, Hwa Jeong
Park, So-Jung
Park, Hyun-Ju
Lee, Kiho
Sheen, Yhun Yhong
Kim, Dae-Kee
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (10) : 4213 - 4238
[23] Ethyl 2-[5-(4-fluorophenyl)pyridin-3-yl]1-[3-(2-oxopyrrolidin-1-yl) propyl]-1H-benzimidazole-5-carboxylate
Yeong, Keng Yoon
Ali, Mohamed Ashraf
Choon, Tan Soo
Rosli, Mohd Mustaqim
Razak, Ibrahim Abdul
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2013, 69 : O1013 - +
[24] 4-{3-[(Pyridin-4-ylmethyl)amino]-[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}phenol: An improved anticancer agent in hepatocellular carcinoma and a selective MDR1/MRP modulator
Khatir, Zahra Zakeri
Di Sotto, Antonella
Percaccio, Ester
Tuylu Kucukkilinc, Tuba
Ercan, Ayse
Chippindale, Ann M.
Valipour, Mehdi
Irannejad, Hamid
ARCHIV DER PHARMAZIE, 2024, 357 (06)
[25] 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2hydroxyimino-N'-[1-(pyridin-2-yl)ethylidene]acetohydrazide
Plutenko, Maxym O.
Lampeka, Rostislav D.
Haukka, Matti
Nordlander, Ebbe
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2012, 68 : O3381 - +
[26] 4-[5-Amino-4-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile
Abu Thaher, Bassam
Koch, Pierre
Schollmeyer, Dieter
Laufer, Stefan
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2012, 68 : O935 - +
[27] 4-(4-Fluorophenyl)-1-(4-nitrophenyl)3-(pyridin-4-yl)-1H-pyrazol-5-amine
Abu Thaher, Bassam
Koch, Pierre
Schollmeyer, Dieter
Laufer, Stefan
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2012, 68 : O633 - U1597
[28] 3D-QSAR Studies on 4-([1,2,4]Triazolo[1,5-α]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole Analogues as Potent Inhibitors of Transforming Growth Factor-β Type Ⅰ Receptor Kinase
孙丽倩
孟利强
闫超群
崔东晓
苗俊秋
陈景润
梁泰刚
李青山
结构化学, 2018, 37 (04) : 517 - 530
[29] 1-(4,5-Dihydro-3-p-tolyl-1H-pyrazol-1-yl)-2-(1,2,4-triazol-1-yl)ethanone
Xu, LZ
Huang, YW
Yang, YX
Zhang, PY
Li, K
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2005, 61 : O3587 - O3588
[30] Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity
Boezio, Alessandro A.
Copeland, Katrina W.
Rex, Karen
Albrecht, Brian K.
Bauer, David
Bellon, Steven F.
Boezio, Christiane
Broome, Martin A.
Choquette, Deborah
Coxon, Angela
Dussault, Isabelle
Hirai, Satoko
Lewis, Richard
Lin, Min-Hwa Jasmine
Lohman, Julia
Liu, Jingzhou
Peterson, Emily A.
Potashman, Michele
Shimanovich, Roman
Teffera, Yohannes
Whittington, Douglas A.
Vaida, Karma
Harmange, Jean-Christophe
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (06) : 2328 - 2342

← 1 2 3 4 5 →