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Development of a prodrug of hydantoin based TACE inhibitor.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Aug 15; Vol. 27 (16), pp. 3704-3708. Date of Electronic Publication: 2017 Jul 03. - Publication Year :
- 2017
-
Abstract
- 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.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- ADAM17 Protein metabolism
Administration, Oral
Animals
Area Under Curve
Dogs
Enzyme Activation drug effects
Half-Life
Haplorhini
Humans
Hydantoins administration & dosage
Hydantoins pharmacokinetics
Pentanoic Acids administration & dosage
Pentanoic Acids pharmacokinetics
Prodrugs administration & dosage
Prodrugs pharmacokinetics
ROC Curve
Rats
Structure-Activity Relationship
ADAM17 Protein antagonists & inhibitors
Hydantoins chemical synthesis
Hydantoins chemistry
Hydantoins pharmacology
Pentanoic Acids chemistry
Prodrugs chemical synthesis
Prodrugs pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 27
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 28711352
- Full Text :
- https://doi.org/10.1016/j.bmcl.2017.07.007