Discovery of N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects

Q1 · MEDICINE

Article

Author: Lou, Changgang ; Adams, Christopher M. ; Liang, Guiqing ; Jeng, Arco Y. ; Gan, Lu ; Singh, Alok K. ; Russell, Kerry S. ; Beil, Michael E. ; Ksander, Gary M. ; Vest, John A. ; LaSala, Daniel ; Fu, Fumin ; Chen, Wei ; Watson, Catherine ; Papillon, Julien P. N. ; Leung-Chu, Jennifer ; Hu, Chii-Whei ; Rigel, Dean F.

Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699's low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8.

13 Aug 2015·ACS medicinal chemistry lettersQ3 · MEDICINE

Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

Q3 · MEDICINE

Article

Author: Castro-Perez, Jose ; Tang, Wei ; Rosenbach, Mark ; Sok, Andrea ; Ma, Xiuying ; Bopp, Charlene ; Zhou, Gaochao ; London, Clare ; Ren, Ning ; Metzger, Joe ; Wisniewski, Tom ; Maxwell, Carrie Ann ; Yin, Lina ; Struthers, Mary ; Verras, Andreas ; van Koppen, Chris J. ; Hu, Qingzhong ; Salituro, Gino ; Stribling, Sloan ; Chen, Qing ; Lassman, Mike ; Hoyt, Scott B. ; Gibson, Jack ; Hajdu, Richard ; McMasters, Daniel ; Clemas, Joe ; Cai, Tian-Quan ; Xiong, Yusheng ; McLaughlin, Theresa ; Szeto, Daphne ; Hartmann, Rolf W. ; Tata, Jim ; Tung, Elaine ; Liang, Gui-Bai ; Forrest, Gail ; Petrilli, Whitney ; Pai, Lee-Yuh ; Buist, Nicole

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

03 Aug 2015·Expert opinion on therapeutic patentsQ2 · MEDICINE

Advances in the treatment of chronic wounds: a patent review

Q2 · MEDICINE

Review

Author: Hartmann, Rolf W. ; van Koppen, Chris J.

INTRODUCTION:

About 2% of the Western world population suffer from chronic wounds, resulting from underlying disorders (e.g., diabetes, excessive pressure, vascular insufficiencies and vasculitis), with a significant adverse effect on Quality of Life. Despite high incidence and economic burden, management of chronic wounds is still far from effective and novel therapies are in urgent need. Wound healing is a dynamic process of transient expression, function and clearance of mediators, enzymes and cell types. Failure to initiate, terminate or regulate leads to pathologic wound healing.

AREAS COVERED:

The present review discusses patents of the seven most promising classes of biological agents, mostly published in 2009 - 2014 (CYP11B1 inhibitors, peptide growth factors, prolyl-4-hydroxylase and matrix metalloproteinase inhibitors, bone marrow-derived mesenchymal stem cells, elastase and connexin43 inhibitors). Relevant information from peer-reviewed journals is also presented.

EXPERT OPINION:

The aforementioned biological agents have different mechanisms of action, and considering the multifactorial pathogenesis of chronic wounds, they hold promise in treating chronic wounds. However, as administration of a certain biological agent may be beneficial in an early phase, it may slow down wound healing in a later phase. Basic and clinical research on chronic wound healing should therefore investigate the efficacy of these agents, alone and in concert, during the consecutive phases of wound healing.

100 Deals associated with CYP11B2 inhibitors (ElexoPharm)

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Preclinical	Germany	ELEXOPHARM GmbH	-
Fibrosis	Preclinical	United States	Angion Biomedica Corp.	-

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