Creation of Novel Cores for β‑Secretase (BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy

In order to find optimal core structures as starting points for lead optimization, a multiparameter lead generation workflow was designed with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer’s disease. De novo design of core fragments was connected with three predictive in silico models addressing target affinity, permeability, and hERG activity, in order to guide synthesis. Taking advantage of an additive SAR, the prioritized cores were decorated with a few, well-characterized substituents from known BACE-1 inhibitors in order to allow for core-to-core comparisons. Prediction methods and analyses of how physicochemical properties of the core structures correlate to in vitro data are described. The syntheses and in vitro data of the test compounds are reported in a separate paper by Ginman et al. [<i>J. Med. Chem.</i> <b>2013</b>, <i>56</i>, 4181–4205]. The affinity predictions are described in detail by Roos et al. [<i>J. Chem. Inf.</i> <b>2014</b>, DOI: 10.1021/ci400374z]

Exploration and Pharmacokinetic Profiling of Phenylalanine Based Carbamates as Novel Substance P 1–7 Analogues

The bioactive metabolite of Substance P, the heptapeptide SP_1–7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP_1–7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP_1–7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH₂ as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH₂ by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP_1–7 analogues with good binding affinities is reported. Extensive <i>in vitro</i> as well as <i>in vivo</i> PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide

Substituted 7‑Amino-5-thio-thiazolo[4,5‑<i>d</i>]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX₃CR1)

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-<i>d</i>]­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 <b>18a</b> and <b>24h</b>. We show the preparation of the first potent and selective orally available CX₃CR1 antagonists