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Literature DB >> 25516791

Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate.

Christian Harcken¹, Doris Riether¹, Pingrong Liu¹, Hossein Razavi¹, Usha Patel¹, Thomas Lee¹, Todd Bosanac¹, Yancey Ward¹, Mark Ralph¹, Zhidong Chen¹, Donald Souza¹, Richard M Nelson¹, Alison Kukulka¹, Tazmeen N Fadra-Khan¹, Ljiljana Zuvela-Jelaska¹, Mita Patel¹, David S Thomson¹, Gerald H Nabozny¹.

Abstract

A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.

Entities: Gene

Keywords: Glucocorticoid mimetics; anti-inflammatory agents; azaindoles; drug-like properties; glucocorticoid-induced osteoporosis; nonsteroidal glucocorticoids

Year: 2014 PMID： 25516791 PMCID： PMC4265816 DOI： 10.1021/ml500387y

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

20 in total

Review 1. The glucocorticoid receptor: molecular mechanism and new therapeutic opportunities.

Authors: Leonard Buckbinder; Ralph P Robinson
Journal: Curr Drug Targets Inflamm Allergy Date: 2002-06

2. Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.

Authors: Raj Betageri; Thomas Gilmore; Daniel Kuzmich; Thomas M Kirrane; Jörg Bentzien; Dieter Wiedenmayer; Younes Bekkali; John Regan; Angela Berry; Bachir Latli; Alison J Kukulka; Tazmeen N Fadra; Richard M Nelson; Susan Goldrick; Ljiljana Zuvela-Jelaska; Don Souza; Josephine Pelletier; Roger Dinallo; Mark Panzenbeck; Carol Torcellini; Heewon Lee; Edward Pack; Christian Harcken; Gerald Nabozny; David S Thomson
Journal: Bioorg Med Chem Lett Date: 2011-09-10 Impact factor: 2.823

3. Nonsteroidal dissociated glucocorticoid agonists containing azaindoles as steroid A-ring mimetics.

Authors: Doris Riether; Christian Harcken; Hossein Razavi; Daniel Kuzmich; Thomas Gilmore; Jörg Bentzien; Edward J Pack; Donald Souza; Richard M Nelson; Alison Kukulka; Tazmeen N Fadra; Ljiljana Zuvela-Jelaska; Josephine Pelletier; Roger Dinallo; Mark Panzenbeck; Carol Torcellini; Gerald H Nabozny; David S Thomson
Journal: J Med Chem Date: 2010-09-23 Impact factor: 7.446

4. Quinol-4-ones as steroid A-ring mimetics in nonsteroidal dissociated glucocorticoid agonists.

Authors: John Regan; Thomas W Lee; Renée M Zindell; Younes Bekkali; Jörg Bentzien; Thomas Gilmore; Abdelhakim Hammach; Thomas M Kirrane; Alison J Kukulka; Daniel Kuzmich; Richard M Nelson; John R Proudfoot; Mark Ralph; Josephine Pelletier; Donald Souza; Lijiljana Zuvela-Jelaska; Gerald Nabozny; David S Thomson
Journal: J Med Chem Date: 2006-12-28 Impact factor: 7.446

Review 5. The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis.

Authors: F Buttgereit; K G Saag; M Cutolo; J A P da Silva; J W J Bijlsma
Journal: Scand J Rheumatol Date: 2005 Impact factor: 3.641

Review 6. Selective Glucocorticoid Receptor modulators.

Authors: Karolien De Bosscher
Journal: J Steroid Biochem Mol Biol Date: 2010-03-04 Impact factor: 4.292

7. A concise asymmetric route for the synthesis of a novel class of glucocorticoid mimetics containing a trifluoromethyl-substituted alcohol.

Authors: Thomas W Lee; John R Proudfoot; David S Thomson
Journal: Bioorg Med Chem Lett Date: 2005-11-02 Impact factor: 2.823

8. Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore.

Authors: Hossein Razavi; Doris Riether; Christian Harcken; Jörg Bentzien; Roger M Dinallo; Donald Souza; Richard M Nelson; Alison Kukulka; Tazmeen N Fadra-Khan; Edward J Pack; Ljiljana Zuvela-Jelaska; Josephine Pelletier; Mark Panzenbeck; Carol A Torcellini; John R Proudfoot; Gerald H Nabozny; David S Thomson
Journal: Bioorg Med Chem Lett Date: 2014-03-12 Impact factor: 2.823

Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate.

Review 1. The glucocorticoid receptor: molecular mechanism and new therapeutic opportunities.

2. Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.

3. Nonsteroidal dissociated glucocorticoid agonists containing azaindoles as steroid A-ring mimetics.

4. Quinol-4-ones as steroid A-ring mimetics in nonsteroidal dissociated glucocorticoid agonists.

Review 5. The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis.

Review 6. Selective Glucocorticoid Receptor modulators.

7. A concise asymmetric route for the synthesis of a novel class of glucocorticoid mimetics containing a trifluoromethyl-substituted alcohol.

8. Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore.

9. Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol.

Review 10. Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor.

1. Azaindole therapeutic agents.

Review 2. Pharmacology of Corticosteroids for Diabetic Macular Edema.

3. Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?