An amide-based sulfenamide prodrug of gamma secretase inhibitor BMS–708163 delivers parent drug from an oral conventional solid dosage form in male beagle dog

• Published in: Bioorganic & medicinal chemistry letters 2020-02, Vol.30 (3), p.126856, Article 126856
• Main Authors: Guarino, Victor R., Olson, Richard E., Everlof, J. Gerry, Wang, Nenghui, McDonald, Ivar, Haskell, Roy, Clarke, Wendy, Lentz, Kimberley A.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Capsules - chemistry; Dogs; Drug delivery; Drug Stability; Half-Life; Male; NH-acid; Oral bioavailability; Oxadiazoles - chemistry; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Solubility; Solubilization; Sulfamerazine - chemical synthesis; Sulfamerazine - chemistry; Sulfamerazine - pharmacokinetics; Sulfenamide prodrug; Sulfonamides - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.126856

[Display omitted] The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH–acid from a conventional solid dosage formulation. This proof of concept was established using BMS–708163 (1), a gamma secretase inhibitor containing a weakly acidic primary amide NH-acid as the chemical handle for attaching a series of thiol-based promoieties via a sulfenamide linkage. Aqueous stabilities and solubilities are reported for a series of six sulfenamide prodrugs (2–7) of 1. The sulfenamide prodrug containing the cysteine methyl ester promoiety (5) was chosen for a orally-dosed PK study in male beagle dog comparing a solubilized formulation of 1 against a solid dosage form of 5 in a cross-over fashion at an equivalent molar dose of 3 mg/kg. Prodrug 5 delivered essentially a superimposable PK profile of 1 compared to the solubilized formulation of 1, without any detectable exposure of 5 in systemic circulation.