Literature DB >> 31620239

Building Bridges in a Series of Estrogen Receptor Degraders: An Application of Metathesis in Medicinal Chemistry.

James S Scott1, Jason Breed2, Rodrigo J Carbajo1, Paul R Davey1, Ryan Greenwood1, Hoan K Huynh3, Teresa Klinowska1, Christopher J Morrow1, Thomas A Moss1, Radoslaw Polanski2, J Willem M Nissink1, Jeffrey Varnes3, Bin Yang3.   

Abstract

Herein we report the use of metathesis to construct a novel tetracyclic core in a series of estrogen receptor degraders. This improved the chemical stability, as assessed using an NMR-MS based assay, and gave a molecule with excellent physicochemical properties and pharmacokinetics in rat. X-ray crystallography established minimal perturbation of the bridged compounds relative to the unbridged analogues in the receptor binding pocket. Unfortunately, despite retaining excellent binding to ERα, this adversely affected the ability of the compounds to degrade the receptor.
Copyright © 2019 American Chemical Society.

Entities:  

Year:  2019        PMID： 31620239      PMCID： PMC6792171          DOI： 10.1021/acsmedchemlett.9b00370

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  18 in total

1.  Prediction of drug candidates' sensitivity toward autoxidation: computational estimation of C-H dissociation energies of carbon-centered radicals.

Authors:  Thomas Andersson; Anders Broo; Emma Evertsson
Journal:  J Pharm Sci       Date:  2014-05-13       Impact factor: 3.534

2.  Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.

Authors:  Steven Harper; John A McCauley; Michael T Rudd; Marco Ferrara; Marcello DiFilippo; Benedetta Crescenzi; Uwe Koch; Alessia Petrocchi; M Katharine Holloway; John W Butcher; Joseph J Romano; Kimberly J Bush; Kevin F Gilbert; Charles J McIntyre; Kevin T Nguyen; Emanuela Nizi; Steven S Carroll; Steven W Ludmerer; Christine Burlein; Jillian M DiMuzio; Donald J Graham; Carolyn M McHale; Mark W Stahlhut; David B Olsen; Edith Monteagudo; Simona Cianetti; Claudio Giuliano; Vincenzo Pucci; Nicole Trainor; Christine M Fandozzi; Michael Rowley; Paul J Coleman; Joseph P Vacca; Vincenzo Summa; Nigel J Liverton
Journal:  ACS Med Chem Lett       Date:  2012-03-02       Impact factor: 4.345

3.  A Screening Assay Cascade to Identify and Characterize Novel Selective Estrogen Receptor Downregulators (SERDs).

Authors:  Rowena Callis; Alfred Rabow; Michael Tonge; Robert Bradbury; Mairi Challinor; Karen Roberts; Karen Jones; Graeme Walker
Journal:  J Biomol Screen       Date:  2015-04-07

4.  Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility.

Authors:  Jane Guan; Wei Zhou; Marc Hafner; Robert A Blake; Cecile Chalouni; Irene P Chen; Tom De Bruyn; Jennifer M Giltnane; Steven J Hartman; Amy Heidersbach; Rene Houtman; Ellen Ingalla; Lorn Kategaya; Tracy Kleinheinz; Jun Li; Scott E Martin; Zora Modrusan; Michelle Nannini; Jason Oeh; Savita Ubhayakar; Xiaojing Wang; Ingrid E Wertz; Amy Young; Mamie Yu; Deepak Sampath; Jeffrey H Hager; Lori S Friedman; Anneleen Daemen; Ciara Metcalfe
Journal:  Cell       Date:  2019-07-25       Impact factor: 41.582

Review 5.  Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment.

Authors:  Hitisha K Patel; Teeru Bihani
Journal:  Pharmacol Ther       Date:  2017-12-28       Impact factor: 12.310

6.  Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927.

Authors:  Mehmet Kahraman; Steven P Govek; Johnny Y Nagasawa; Andiliy Lai; Celine Bonnefous; Karensa Douglas; John Sensintaffar; Nhin Liu; KyoungJin Lee; Anna Aparicio; Josh Kaufman; Jing Qian; Gang Shao; Rene Prudente; James D Joseph; Beatrice Darimont; Daniel Brigham; Richard Heyman; Peter J Rix; Jeffrey H Hager; Nicholas D Smith
Journal:  ACS Med Chem Lett       Date:  2018-12-06       Impact factor: 4.345

7.  Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.

Authors:  George S Tria; Tinya Abrams; Jason Baird; Heather E Burks; Brant Firestone; L Alex Gaither; Lawrence G Hamann; Guo He; Christina A Kirby; Sunkyu Kim; Franco Lombardo; Kaitlin J Macchi; Donald P McDonnell; Yuji Mishina; John D Norris; Jill Nunez; Clayton Springer; Yingchuan Sun; Noel M Thomsen; Chunrong Wang; Jianling Wang; Bing Yu; Choi-Lai Tiong-Yip; Stefan Peukert
Journal:  J Med Chem       Date:  2018-03-22       Impact factor: 7.446

8.  Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.

Authors:  Chris De Savi; Robert H Bradbury; Alfred A Rabow; Richard A Norman; Camila de Almeida; David M Andrews; Peter Ballard; David Buttar; Rowena J Callis; Gordon S Currie; Jon O Curwen; Chris D Davies; Craig S Donald; Lyman J L Feron; Helen Gingell; Steven C Glossop; Barry R Hayter; Syeed Hussain; Galith Karoutchi; Scott G Lamont; Philip MacFaul; Thomas A Moss; Stuart E Pearson; Michael Tonge; Graeme E Walker; Hazel M Weir; Zena Wilson
Journal:  J Med Chem       Date:  2015-10-07       Impact factor: 7.446

9.  A synthesis of chiral 1,1,3-trisubstituted 1,2,3,4-tetrahydro-beta-carbolines by the Pictet-Spengler reaction of tryptophan and ketones: conversion of (1R,3S)-diastereomers into their (1S,3S)-counterparts by scission of the C(1)-N(2) bond.

Authors:  Yoshie Horiguchi; Masayoshi Nakamura; Toshiaki Saitoh; Takehiro Sano
Journal:  Chem Pharm Bull (Tokyo)       Date:  2003-12       Impact factor: 1.645

10.  RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models.

Authors:  Fiona Garner; Maysoun Shomali; Dotty Paquin; C Richard Lyttle; Gary Hattersley
Journal:  Anticancer Drugs       Date:  2015-10       Impact factor: 2.248
View more

北京卡尤迪生物科技股份有限公司 © 2022-2023.