2-Amino-3,4-dihydroquinazolines as Inhibitors of BACE-1 (β-Site APP Cleaving Enzyme):  Use of Structure Based Design to Convert a Micromolar Hit into a Nanomolar Lead

Abstract

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

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

“…11). The optimization of a similar 2-aminoquinazoline scaffold has also recently been reported [Baxter et al, 2007]. In this case, the initial lead (K i 5 0.9 mM) was identified via a high-throughput screen (HTS) of the Johnson & Johnson corporate compound collection.…”

“…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.…”

“…Other studies that demonstrate at least some brain penetration of BACE-1 inhibitors include Chang et al [2004] and Hussain et al [2007]. An increased focus on highthroughput and fragment-based screening approaches has also led to the discovery of more compact, lower molecular weight BACE-1 inhibitors [Baxter et al, 2007;Congreve et al, 2007;.…”

L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases β-amyloid peptide production in HEK293-APPswe cells

“…Another class of non-peptidic BACE1 inhibitors were obtained from a highthroughput screening (HTS) technology-based assay targeting chemical libraries. Typical examples of this class of inhibitors include compounds 10d [26] , 3a [27] , and TAK-070 [28] , which are orally active and show good selectivity over other aspartic proteases. The third class of BACE1 inhibitors includes natural products, such as catechins obtained from Green tea [29] , lavandulyl flavanones extracted from Sophora flavescens [30] , resveratrol obtained from Vitis vinifera [31] and TDC obtained from Glycyrrhiza glabra [32] .…”

Discovery of Biphenylacetamide-Derived Inhibitors of BACE1 Using de Novo Structure-Based Molecular Design

“…11 More recently, the application of high-throughput screening approaches has led to the identification of non-peptide BACE1 inhibitors. [12][13][14] A complementary strategy for BACE1 inhibitor discovery is the application of computer-aided methods to design small-molecule non-peptidic inhibitors using X-ray crystallographic structures of BACE1.…”