Design and synthesis of statine-Containing BACE inhibitors

Advances in the identification of β-secretase inhibitors

“…Researchers at Eli Lilly disclosed a series of peptidic BACE1 inhibitors (e.g., 10 and 11, IC 50 = 86 and 28 nM, respectively, Figure 3) with a statine or hydroxyethylene unit as a substrate transitionstate analog [50,52]. The authors reported a series of potent BACE1 inhibitors (e.g., 12a, 12b and 13, IC 50 = 3.9, 1.2 and 5.6 nM, respectively, Figure 3) with an HMC isostere as a transition-state analog [53][54][55][56][57][58].…”

Recent progress in the drug discovery of non-peptidic BACE1 inhibitors

“…Furthermore, we reported a more potent BACE1 inhibitor KMI-684 (IC 50 = 1.2 nM) with two carboxylic acid bioisosteres at the P 1 ′ position, and KMI-574 (IC 50 = 5.6 nM) that showed improved inhibitory activity in cultured cells [21][22][23]. Concurrently, some peptide-type BACE1 inhibitors with a transition-state analogue were reported by other research groups, for example, Boyd et al [24] (Pfizer), Hu et al [25] (Eli Lilly), Tung et al [26] (Elan Pharmaceuticals) and Tamamura et al [27] (Kyoto University). However, these peptide-type inhibitors had large molecular sizes and have not been evaluated for the membrane permeability across the brood-brain barrier and in vivo enzymatic stability.…”

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

“…Several examples are shown in Figure 10. These can be roughly classified by their transition state mimic and include: (1) peptidomimetic designs incorporating statine Hu et al, 2003Hu et al, , 2004Lamar et al, 2004;Tung et al, 2002], hydroxymethylcarbonyl [Hamada et al, 2006[Hamada et al, , 2008aShuto et al, 2003], or hydroxyethylene [Brady et al, 2004;Ghosh et al, 2006;Hanessian et al, 2005;Hom et al, 2004;Xiao et al, 2006]; (2) nonpeptidic designs incorporating a reduced amide , hydroxymethylcarbonyl [Hamada et al, 2008a,b] hydroxyethylene [Ghosh et al, 2007], hydroxyethylamine Freskos et al, 2007a,b;Ghosh et al, 2008;Kortum et al, 2007;Maillard et al, 2007;Park et al, 2008;Stachel et al, 2004Stachel et al, , 2006Stauffer et al, 2007], aminoethylene , or tertiary carbinamine [Lindsley et al, 2007;Rajapakse et al, 2006]; (3) arylpiperazines [Garino et al, 2006]; (4) acylguanidines Fobare et al, 2007;Jennings et al, 2008]; (5) dihydroquinazolines [Baxter et al, 2007]; (6) isocytosines Geschwindner et al, 2007]; (7) pyrrolidine/piperidines [Iserloh et al,Fig. 9.…”