Isosorbide-based cholinesterase inhibitors; replacement of 5-ester groups leading to increased stability

Abstract

Isosorbide-2-carbamate-5-esters are highly potent and selective butyrylcholinesterase inhibitors with potential utility in the treatment of Alzheimer's Disease (AD). They are stable in human plasma but in mouse plasma they undergo hydrolysis at the 5-ester group potentially attenuating in vivo potency. In this paper we explore the role of the 5-position in modulating potency. The focus of the study was to increase metabolic stability while preserving potency and selectivity. Dicarbamates and 5-keto derivatives were markedly less potent than the ester class. The 2-benzylcarbamate-5-benzyl ether was found to be potent (IC 50 52 nM) and stable in the presence of mouse plasma and liver homogenate. The compound produces sustained moderate inhibition of mouse butyrylcholinesterase at 1 mg/kg, IP.

Catalytic access to anhydrohexitols and their isomerization

“…The release of isoidide was performed by aqueous hydrolysis of the acetates (no detailed experimental part, no yield given). 83 Scheme 12 Synthesis of isoidide through activation/SN2 reaction 83…”

Asymmetric Iodoetherification of Isosorbide-Derived Glycals: A Regio- and Stereoselective Access to a Variety of O-Substituted Isosorbide Derivatives

“…In the same way, isosorbide 1 can be regioselectively monoacetylated at the endo position using acetic anhydride in the presence of catalytic amount of lead(II) oxide to afford 5b in high yield [27]. Conversion to the corresponding glycals 4a [7,28] and 4b [3,4] was achieved by a two-step process: preliminary conversion to their triflate derivatives followed by in situ elimination of the triflate moiety with 1,8diazabicyclo [5.4.0]undec-7-ene (DBU) [29]. It is noteworthy to mention that glycals 4a,b are stable under neutral conditions and could be purified by flash chromatography.…”

Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer’s Disease

“…Isosorbide-2-alkyl and aryl carbamates are selective and potent inhibitors of BuChE (e.g., 1 in Figure 1, IC 50 BuChE 4.3 nM), and they are selective for BuChE over AChE and related carboxylesterases including CE1 and CE2 found in human liver and intestine [22]. Whereas the 2-carbamate is essential to activity, we showed that the 5-position of the isosorbide scaffold could be modified in diverse ways producing more or less potent compounds [23]. We hypothesised that it might be possible to retain the inhibitory isosorbide-2-carbamate functionality but substitute the effective 5-benzoate in 1 with lipoic acid or ferulic acid esters, retaining cholinesterase sub-type selectivity while introducing new disease modifying functionality as shown in Figure 1.…”