The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aβ40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 μM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of β-amyloid peptides in mouse brain following oral dosing.

We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.

A spacer-equipped tetrasaccharide, p-aminocyclohexylethyl alpha-l-Colp-(1-->2)-beta-d-Galp-(1-->3)-[alpha-l-Colp-(1-->4)]-beta-D-GlcpNAc, containing a 4,6-cyclic phosphate in the galactose residue, has been synthesised. The structure corresponds to a part of the repeating unit of the capsular (and lipo-) polysaccharide of the endemic bacteria Vibrio cholerae type O139 synonym Bengal. The synthetic strategy allows continuous syntheses of the complete O139 hexasaccharide repeating unit as well as of the structurally related repeating unit of serotype O22. Starting from ethyl 2-azido-4,6-O-benzylidene-2-deoxy-1-thio-beta-D-glucopyranoside, a thioglycoside tetrasaccharide donor block was constructed through two orthogonal glycosylations with glycosyl bromide donors. First, a properly protected galactose moiety was introduced using silver triflate as promoter and subsequently the two colitose residues, carrying electron-withdrawing protecting groups for stability reasons, under halide-assisted conditions. The tetrasaccharide block was then linked to the spacer in a NIS-TMSOTf-promoted coupling. Transformation of the azido group into an acetamido group using H2S followed by removal of temporary protecting acetyl groups gave a 4',6'-diol, which was next phosphorylated with methyl dichlorophosphate and deprotected to yield the 4,6-cyclic phosphate tetrasaccharide target structure.

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