Abstract
Compound 4 (PF-04971729) belongs to a new class
of potent and selective sodium-dependent glucose cotransporter 2 inhibitors
incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system.
In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4.
This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.
Citing Articles
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This article has been cited by 4 ACS Journal articles (4 most recent appear below).
Design, Synthesis, and Biological Evaluation of Deuterated C-Aryl Glycoside as a Potent and Long-Acting Renal Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes
Ge Xu, Binhua Lv, Jacques Y. Roberge, Baihua Xu, Jiyan Du, Jiajia Dong, Yuanwei Chen, Kun Peng, Lili Zhang, Xinxing Tang, Yan Feng, Min Xu, Wei Fu, Wenbin Zhang, Liangcheng Zhu, Zhongping Deng, Zelin Sheng, Ajith Welihinda, and Xun SunJournal of Medicinal Chemistry2014 57 (4), 1236-1251Design, Synthesis, and Biological Evaluation of Deuterated C-Aryl Glycoside as a Potent and Long-Acting Renal Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes
GeXu, BinhuaLv, Jacques Y.Roberge, BaihuaXu, JiyanDu, JiajiaDong, YuanweiChen, KunPeng, LiliZhang, XinxingTang, YanFeng, MinXu, WeiFu, WenbinZhang, LiangchengZhu, ZhongpingDeng, ZelinSheng, AjithWelihinda, and XunSunJournal of Medicinal Chemistry2014 57 (4), 1236-1251SGLT2 inhibitors deuterated at sites susceptible to oxidative metabolism were found to have a slightly longer tmax and half-life (t1/2), dose-dependent increase in urinary glucose excretion (UGE) in rats, and slightly superior effects on UGE in dogs while ...
Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin
David Bernhardson, Thomas A. Brandt, Catherine A. Hulford, Richard S. Lehner, Brian R. Preston, Kristin Price, John F. Sagal, Michael J. St. Pierre, Peter H. Thompson, and Benjamin ThumaOrganic Process Research & Development2014 18 (1), 57-65Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin
DavidBernhardson, Thomas A.Brandt, Catherine A.Hulford, Richard S.Lehner, Brian R.Preston, KristinPrice, John F.Sagal, Michael J.St. Pierre, Peter H.Thompson, and BenjaminThumaOrganic Process Research & Development2014 18 (1), 57-65The development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, ertugliflozin, for the treatment of type-2 diabetes is described. Highlights of the chemistry are a concise, four-step synthesis of a ...
Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin
Paul Bowles, Steven J. Brenek, Stéphane Caron, Nga M. Do, Michele T. Drexler, Shengquan Duan, Pascal Dubé, Eric C. Hansen, Brian P. Jones, Kris N. Jones, Tomislav A. Ljubicic, Teresa W. Makowski, Jason Mustakis, Jade D. Nelson, Mark Olivier, Zhihui Peng, Hahdi H. Perfect, David W. Place, John A. Ragan, John J. Salisbury, Corey L. Stanchina, Brian C. Vanderplas, Mark E. Webster, and R. Matt WeeklyOrganic Process Research & Development2014 18 (1), 66-81Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin
PaulBowles, Steven J.Brenek, StéphaneCaron, Nga M.Do, Michele T.Drexler, ShengquanDuan, PascalDubé, Eric C.Hansen, Brian P.Jones, Kris N.Jones, Tomislav A.Ljubicic, Teresa W.Makowski, JasonMustakis, Jade D.Nelson, MarkOlivier, ZhihuiPeng, Hahdi H.Perfect, David W.Place, John A.Ragan, John J.Salisbury, Corey L.Stanchina, Brian C.Vanderplas, Mark E.Webster, and R. MattWeeklyOrganic Process Research & Development2014 18 (1), 66-81A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane ...
Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes
Yoshihito Ohtake, Tsutomu Sato, Takamitsu Kobayashi, Masahiro Nishimoto, Naoki Taka, Koji Takano, Keisuke Yamamoto, Masayuki Ohmori, Marina Yamaguchi, Kyoko Takami, Sang-Yong Yeu, Koo-Hyeon Ahn, Hiroharu Matsuoka, Kazumi Morikawa, Masayuki Suzuki, Hitoshi Hagita, Kazuharu Ozawa, Koji Yamaguchi, Motohiro Kato, and Sachiya IkedaJournal of Medicinal Chemistry2012 55 (17), 7828-7840
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