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.

A new palladium-dipyridylmethylamine complex is an excellent catalyst for C-C bond-forming processes such as the Heck, Suzuki, and Sonogashira reactions in organic and aqueous solvents under homogeneous conditions. [reaction: see text]

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Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40-50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.

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.

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Di(2-pyridyl)methylamine-based palladium dichloride complexes 4 are versatile catalysts for different types of cross-coupling reactions in water or aqueous solvents under aerobic conditions. The Suzuki-Miyaura reaction of arylboronic acids can be performed with bromoarenes under water reflux using K 2 CO 3 as base or at room temperature or 60 8C in aqueous methanol using KOH as base. For aryl chlorides the corresponding cross-couplings with arylboronic acids can be carried out in refluxing water with K 2 CO 3 as base and TBAB as additive to provide biaryls and heterobiaryls. Arylboronic acids react with benzylic chlorides and allylic substrates such as chlorides, acetates or carbonates also in refluxing water with K 2 CO 3 as base or at room temperature in aqueous acetone and KOH as base, to give diarylmethanes and arylpropenes. Trimethylboroxine and alkylboronic acids are coupled with bromo-and chloroarenes under water at reflux with K 2 CO 3 as base and TBAB as additive to furnish methyl-and butylarenes. These cross-couplings have also been performed in shorter times under microwave irradiation. Several important intermediates such as, 4'-methylbiphenyl-2-carbonitrile, 4-biphenylacetic acid, 3-(3-methylphenyl)benzoic acid, 4,5-diphenyl-2-methyl-3(2H)pyridazinone and 2-(4'-fluorobenzyl)thiophene have been prepared under aqueous and aerobic conditions in good yields.

A␤, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). ␤-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to A␤ peptides. Small molecule BACE1 inhibitors are expected to decrease A␤-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC 50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of A␤ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.