当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > 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.

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.

Abstract：

: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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Guarino VR,Olson RE,Everlof JG,Wang N,McDonald I,Haskell R,Clarke W,Lentz KA

doi

10.1016/j.bmcl.2019.126856

subject

Has Abstract

pub_date

2020-02-01 00:00:00

pages

126856

issue

3

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(19)30830-3

journal_volume

30

pub_type

杂志文章

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