Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors

Ling Tong; Seong Heon Kim; Kristin Rosner; Wensheng Yu; Bandarpalle B Shankar; Lei Chen; Dansu Li; Chaoyang Dai; Vinay Girijavallabhan; Janeta Popovici-Muller; Liping Yang; Guowei Zhou; Aneta Kosinski; M Arshad Siddiqui; Neng-Yang Shih; Zhuyan Guo; Peter Orth; Shiying Chen; Daniel Lundell; Xiaoda Niu; Shelby Umland; Joseph A Kozlowski

doi:10.1016/j.bmcl.2017.05.062

Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors

Bioorg Med Chem Lett. 2017 Jul 15;27(14):3037-3042. doi: 10.1016/j.bmcl.2017.05.062. Epub 2017 May 22.

Authors

Ling Tong¹, Seong Heon Kim², Kristin Rosner², Wensheng Yu², Bandarpalle B Shankar², Lei Chen², Dansu Li², Chaoyang Dai², Vinay Girijavallabhan², Janeta Popovici-Muller², Liping Yang², Guowei Zhou², Aneta Kosinski², M Arshad Siddiqui², Neng-Yang Shih², Zhuyan Guo³, Peter Orth², Shiying Chen⁴, Daniel Lundell⁵, Xiaoda Niu⁵, Shelby Umland⁵, Joseph A Kozlowski⁶

Affiliations

¹ Department of Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: [email protected].
² Department of Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
³ Department of Chemistry, Modeling and Informatics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁴ Department of Pharmacokinetics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁵ Department of Immunology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
⁶ Department of Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA; Department of Chemistry, Modeling and Informatics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA; Department of Pharmacokinetics, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA; Department of Immunology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

PMID: 28558971
DOI: 10.1016/j.bmcl.2017.05.062

Abstract

We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.

Keywords: Hydantoin; TACE inhibitors; Tumor necrosis factor-alpha.

MeSH terms

ADAM17 Protein / antagonists & inhibitors*
ADAM17 Protein / metabolism
Animals
Area Under Curve
Dogs
Enzyme Activation / drug effects
Half-Life
Haplorhini
Humans
Hydantoins / chemical synthesis
Hydantoins / chemistry*
Hydantoins / pharmacology
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology
ROC Curve
Rats
Structure-Activity Relationship

Substances

Hydantoins
Protease Inhibitors
ADAM17 Protein
ADAM17 protein, human