The Medicinal Chemistry of Glucocorticoid Receptor Modulators

This book covers the design and development of glucocorticoid receptor modulators (GRM) from cortisol to antibody-drug conjugate payloads over the last 70 years. The author starts with an introduction to the background of glucocorticoid receptor modulators as potential therapeutic modalities. This is followed by seven chapters in which he collates and discusses the medicinal chemistry journey of GRMs, reviewing topics such as cortisol-based glucocorticoids, the different approaches that have been pursued to enable chronic dosing of GRM compounds by inactivation in plasma and the liver, the application of prodrugs to GRMs, selective GRMs, targeted delivery of GRMs using polymers and nanoparticles, and rational drug design approaches applied in the development of GRMs. Particular attention is given to the development of glucocorticoid receptor modulators as immunology antibody-drug conjugate payloads. In the book's final chapter, the author critiques the medicinal chemistry progress madesince the discovery of cortisone and the promise of the latest antibody-drug conjugates that release a GRM payload. In this book, readers will also find an overview of the X-ray structures of glucocorticoid receptor antagonists and a list of all the earlier reviews that cover part of the medicinal chemistry story of GRM collated by keywords organized in a table. With several examples of crystal structures and molecular modeling, this book illustrates the huge effort by multiple companies and research groups to develop glucocorticoid receptor modulators. Professionals and scholars alike will find it a handy tool, and appreciate the latest research findings that it presents.

Outlines the development of glucocorticoid receptor modulators from 1950 to 2022 Shows how prodrugs and metabolic inactivation are applied to drug discovery Presents Antibody-Drug Conjugates for immunology

Auteur
Adrian Hobson, FRSC, is a Senior Research Fellow at Abbvie, and an adjunct Professor of Chemistry at Clark University in Worcester, MA, USA. With 30 years of experience as a medicinal chemist, he started his journey at Boots Pharmaceuticals, Nottingham UK, where he worked on anti-depressants and anti-psychotics, and in the Special Synthesis group making metabolites and possible impurities. After the company was acquired by BASF in 1994, he formed the High Speed Analoging team, working there for 6 years until he transferred to the BASF Bioresearch Corporation at Worcester, MA, USA, where he formed a new High Speed Analoging team to support both oncology and immunology. He spent the next 12 years working in medicinal chemistry on kinase, GPCR and NHR targets including selective glucocorticoid receptor modulators. When AbbVie split from Abbott, Dr Hobson switched his attention to immunology antibody-drug conjugates, where he has pioneered the use of glucocorticoid receptor modulators (GRM) as a payload for antibody-drug conjugates.

Contenu
Introduction.- cortisol-based glucocorticoids.- metabolically inactivated glucocorticoids.- prodrugs.- selective glucocorticoid receptor modulators.- polymers and particles.- QSAR and Modelling.- Antibody Drug Conjugates.- Conclusion.