Development of a prodrug of hydantoin based TACE inhibitor

[Display omitted] Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges wh...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (16), p.3704-3708
Hauptverfasser:	Tong, Ling, Kim, Seong Heon, Chen, Lei, Kosinski, Aneta, Shankar, Bandarpalle B., Girijavallabhan, Vinay, Yang, De-Yi, Yu, Wensheng, Zhou, Guowei, Shih, Neng-Yang, Chen, Shiying, Hu, Mengwei, Lundell, Daniel, Niu, Xiaoda, Umland, Shelby, Kozlowski, Joseph A.
Format:	Artikel
Sprache:	eng
Schlagworte:	ADAM17 Protein - antagonists & inhibitors ADAM17 Protein - metabolism Administration, Oral Animals Anti-inflammatory agent Area Under Curve Dogs Enzyme Activation - drug effects Half-Life Haplorhini Humans Hydantoin Hydantoins - administration & dosage Hydantoins - chemical synthesis Hydantoins - chemistry Hydantoins - pharmacokinetics Hydantoins - pharmacology Pentanoic Acids - administration & dosage Pentanoic Acids - chemistry Pentanoic Acids - pharmacokinetics Prodrug Prodrugs - administration & dosage Prodrugs - chemical synthesis Prodrugs - pharmacokinetics Prodrugs - pharmacology Rats ROC Curve Structure-Activity Relationship TACE inhibitors
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Zusammenfassung:	[Display omitted] Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2017.07.007