Literature DB >> 34531952

Utilization of Metabolite Identification and Structural Data to Guide Design of Low-Dose IDO1 Inhibitors.

Brett Hopkins1, Hongjun Zhang1, Indu Bharathan1, Derun Li1, Qinglin Pu1, Hua Zhou1, Theodore A Martinot1, Xavier Fradera1, Alfred Lammens2, Charles A Lesburg1, Ryan D Cohen3, Jeanine Ballard1, Ian Knemeyer1, Karin Otte1, Stella Vincent1, J Richard Miller1, Nicolas Solban1, Mangeng Cheng1, Prasanthi Geda1, Nadya Smotrov1, Xuelei Song1, David Jonathan Bennett1, Yongxin Han1.   

Abstract

Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD).
© 2021 American Chemical Society.

Entities:  

Year:  2021        PMID： 34531952      PMCID： PMC8436249          DOI： 10.1021/acsmedchemlett.1c00265

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.632


  20 in total

1.  Design, synthesis, and biological evaluations of novel quinolones as HIV-1 non-nucleoside reverse transcriptase inhibitors.

Authors:  David Ellis; Kelli L Kuhen; Beth Anaclerio; Baogen Wu; Karen Wolff; Hong Yin; Badry Bursulaya; Jeremy Caldwell; Donald Karanewsky; Yun He
Journal:  Bioorg Med Chem Lett       Date:  2006-06-16       Impact factor: 2.823

2.  Volume of Distribution in Drug Design.

Authors:  Dennis A Smith; Kevin Beaumont; Tristan S Maurer; Li Di
Journal:  J Med Chem       Date:  2015-04-01       Impact factor: 7.446

Review 3.  The role of ligand efficiency metrics in drug discovery.

Authors:  Andrew L Hopkins; György M Keserü; Paul D Leeson; David C Rees; Charles H Reynolds
Journal:  Nat Rev Drug Discov       Date:  2014-02       Impact factor: 84.694

4.  Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).

Authors:  Catherine White; Meredeth A McGowan; Hua Zhou; Nunzio Sciammetta; Xavier Fradera; Jongwon Lim; Elizabeth M Joshi; Christine Andrews; Elliott B Nickbarg; Phillip Cowley; Sarah Trewick; Martin Augustin; Konstanze von Köenig; Charles A Lesburg; Karin Otte; Ian Knemeyer; Hyun Woo; Wensheng Yu; Mangeng Cheng; Peter Spacciapoli; Prasanthi Geda; Xuelei Song; Nadya Smotrov; Patrick Curran; Mee Ra Heo; Pravien Abeywickrema; J Richard Miller; David Jonathan Bennett; Yongxin Han
Journal:  ACS Med Chem Lett       Date:  2020-03-10       Impact factor: 4.345

5.  New and easy route to primary cyclopropylamines from nitriles.

Authors:  P Bertus; J Szymoniak
Journal:  Chem Commun (Camb)       Date:  2001-09-21       Impact factor: 6.222

6.  Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.

Authors:  Craig Lammert; Stefan Einarsson; Chandan Saha; Anna Niklasson; Einar Bjornsson; Naga Chalasani
Journal:  Hepatology       Date:  2008-06       Impact factor: 17.425

7.  The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.

Authors:  Tanaji T Talele
Journal:  J Med Chem       Date:  2016-06-30       Impact factor: 7.446

Review 8.  Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?

Authors:  Andrew L Mellor; Henrique Lemos; Lei Huang
Journal:  Front Immunol       Date:  2017-10-27       Impact factor: 7.561

Review 9.  PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome.

Authors:  Hashem O Alsaab; Samaresh Sau; Rami Alzhrani; Katyayani Tatiparti; Ketki Bhise; Sushil K Kashaw; Arun K Iyer
Journal:  Front Pharmacol       Date:  2017-08-23       Impact factor: 5.810

10.  INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology.

Authors:  Eddy W Yue; Richard Sparks; Padmaja Polam; Dilip Modi; Brent Douty; Brian Wayland; Brian Glass; Amy Takvorian; Joseph Glenn; Wenyu Zhu; Michael Bower; Xiangdong Liu; Lynn Leffet; Qian Wang; Kevin J Bowman; Michael J Hansbury; Min Wei; Yanlong Li; Richard Wynn; Timothy C Burn; Holly K Koblish; Jordan S Fridman; Tom Emm; Peggy A Scherle; Brian Metcalf; Andrew P Combs
Journal:  ACS Med Chem Lett       Date:  2017-03-06       Impact factor: 4.345
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  2 in total

1.  Modular Synthesis of Cyclopropane-Fused N-Heterocycles Enabled by Underexplored Diazo Reagents.

Authors:  Matthieu J R Richter; Frédéric J Zécri; Karin Briner; Stuart L Schreiber
Journal:  Angew Chem Int Ed Engl       Date:  2022-04-25       Impact factor: 16.823

2.  Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism.

Authors:  Quanjun Yang; Juan Hao; Mengyi Chi; Yaxian Wang; Bo Xin; Jinglu Huang; Jin Lu; Jie Li; Xipeng Sun; Chunyan Li; Yan Huo; Jianping Zhang; Yonglong Han; Cheng Guo
Journal:  Oncoimmunology       Date:  2022-03-25       Impact factor: 8.110
  2 in total

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