Our research on hydantoin based TNF-a converting enzyme (TACE) inhibitors identified fused bi-heteroaryl hydantoins (e.g. compound 2) as a series that demonstrates sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and reasonable DMPK profiles. Compound 2 was derived from lead 1 by cyclization onto the linking acetylene. However, compound 2 showed less than ideal dose proportionality in rat single rising dose studies and it also posed formulation challenges for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 (SCH 900577) was identified. It demonstrated improved DMPK properties compared with parent compound 2, provided a stable formulation, and was suitable for further development.

Discovery of preclinical candidate SCH 900577: A prodrug of hydantoin based TACE inhibitor

253rd National Meeting (2017)

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