SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORγ Inhibitor

ACS Medicinal Chemistry Letters
Kazuyuki HirataMakoto Shiozaki

Abstract

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.

References

Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·I D KuntzP A Kollman
May 31, 2002·Journal of Medicinal Chemistry·Daniel F VeberKenneth D Kopple
Mar 18, 2004·Bioorganic & Medicinal Chemistry Letters·Shelley AllenLaurence E Burgess
Apr 28, 2004·Drug Discovery Today·Andrew L HopkinsAlexander Alex
Oct 16, 2009·Journal of Medicinal Chemistry·Frank LoveringChristine Humblet
Feb 2, 2012·ACS Chemical Biology·Naresh KumarPatrick R Griffin
Dec 13, 2012·Bioorganic & Medicinal Chemistry Letters·Pasha M KhanTheodore M Kamenecka
Apr 1, 2007·Expert Opinion on Drug Discovery·Cele Abad-Zapatero
Sep 17, 2013·ACS Medicinal Chemistry Letters·Jun R HuhDan R Littman
Nov 19, 2013·Bioorganic & Medicinal Chemistry Letters·Benjamin P FauberHarvey Wong
Feb 8, 2014·Journal of Medicinal Chemistry·Benjamin P Fauber, Steven Magnuson
Apr 2, 2014·Bioorganic & Medicinal Chemistry Letters·Benjamin P FauberHarvey Wong
Jun 6, 2014·ACS Medicinal Chemistry Letters·Ting YangYonghui Wang
Dec 3, 2014·Bioorganic & Medicinal Chemistry Letters·Monique B van NielHarvey Wong
Mar 31, 2015·ACS Medicinal Chemistry Letters·Olivier RenéHarvey Wong

❮ Previous
Next ❯

Citations

Sep 16, 2016·Expert Opinion on Therapeutic Patents·Sarah M BronnerJames J Crawford
May 12, 2017·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Masato NoguchiMasafumi Kamada
Nov 24, 2016·ChemMedChem·Christelle DoebelinTheodore M Kamenecka
Nov 29, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Xiaoliang ZhuoBenjamin M Johnson
Apr 16, 2018·Chemistry : a European Journal·Sergey A ZhershPavel K Mykhailiuk
Jan 26, 2021·Bioorganic & Medicinal Chemistry Letters·Ryota NakajimaSatoshi Shuto
Aug 11, 2018·Journal of Medicinal Chemistry·Frank NarjesThomas G Hansson
Feb 19, 2019·Journal of Medicinal Chemistry·Masayuki KotokuMakoto Shiozaki
Sep 28, 2017·Journal of Agricultural and Food Chemistry·Shasha ZhangShengkun Li

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.