Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1' alkoxy residues and an aminoethylene (AE) central core.

In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1' methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1' pocket by introducing a set of P1' alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1' positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1' positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K(i) values in the range of 1-20 nM, where the most potent compounds featured small P1' groups. The cathepsin D selectivity which was high for the smallest P1' substituents (P1'=ethoxy, fold selectively >1500) dropped for larger groups (P1'=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

[1]  Alison R. Gregro,et al.  Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation. , 2007, Bioorganic & medicinal chemistry letters.

[2]  Abhisek Banerjee,et al.  Synthesis and stereoselective glycosylation of D- and L-glycero-beta-D-manno-heptopyranoses. , 2005, Organic letters.

[3]  Alison R. Gregro,et al.  Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). , 2004, Journal of medicinal chemistry.

[4]  Elizabeth Hamelink,et al.  Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II. Use of solid-phase synthesis to explore novel statine motifs. , 2004, Journal of medicinal chemistry.

[5]  Elizabeth Hamelink,et al.  Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template. , 2006, Bioorganic & medicinal chemistry.

[6]  Synthetic Strategies of Nonpeptidic β-Secretase (BACE1) Inhibitors , 2009 .

[7]  T. Guo,et al.  Development of BACE1 inhibitors for Alzheimer's disease. , 2006, Current medicinal chemistry.

[8]  J. Walker,et al.  Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[10]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[11]  N. Borkakoti,et al.  Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues. , 2008, Bioorganic & medicinal chemistry.

[12]  B. Samuelsson,et al.  HIV-1 protease inhibitors based on acyclic carbohydrates , 1998 .

[13]  M. Bhadbhade,et al.  Sulfonate Protecting Groups: Synthesis of D‐ and L‐myo‐Inositol‐1,3,4,5‐tetrakisphosphate Precursors by a Novel Silver(I) Oxide‐Mediated O‐Alkylation of 2,4(6)‐Di‐O‐acyl‐6(4)‐O‐sulfonyl‐myo‐Inositol 1,3,5‐Orthoformate Derivatives Through Intramolecular Assistance of the Sulfonyl Group , 2003 .

[14]  J. Bemiller,et al.  Methods in Carbohydrate Chemistry , 1965 .

[15]  Romano Silvestri,et al.  Boom in the development of non‐peptidic β‐secretase (BACE1) inhibitors for the treatment of Alzheimer's disease , 2009, Medicinal research reviews.

[16]  D. Hazuda,et al.  Rational design and synthesis of selective BACE-1 inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[17]  R. Whistler,et al.  Synthesis of some derivatives of 6-amino-1,5-anhydro-6-deoxy-D-glucitol and 2-amino-1,5-anhydro-2-deoxy-D-glucitol. , 1986, Carbohydrate research.

[18]  John A. Robinson,et al.  Novel renin inhibitors: synthesis of aminostatine and comparison with statine-containing analogues , 1986 .

[19]  B. Szabó,et al.  KMI-008, a novel beta-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: design and synthesis of substrate-based octapeptides. , 2003, Bioorganic & medicinal chemistry letters.

[20]  Elizabeth Hamelink,et al.  New potent C2-symmetric malaria plasmepsin I and II inhibitors. , 2003, Bioorganic & medicinal chemistry.

[21]  Arun K. Ghosh,et al.  Memapsin 2 (beta-secretase) inhibitors: drug development. , 2008, Current Alzheimer research.

[22]  S. Stachel.  Progress toward the development of a viable BACE‐1 inhibitor , 2009 .

[23]  D. Selkoe,et al.  Translating cell biology into therapeutic advances in Alzheimer's disease , 1999, Nature.

[24]  Design and synthesis of HIV-1 protease inhibitors. Novel tetrahydrofuran P2/P2'-groups interacting with Asp29/30 of the HIV-1 protease. Determination of binding from X-ray crystal structure of inhibitor protease complex. , 2003, Bioorganic & medicinal chemistry.

[25]  Jian Sun,et al.  Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1. , 2006, Journal of medicinal chemistry.

[26]  S. Thaisrivongs,et al.  alpha,alpha-Difluoro-beta-aminodeoxystatine-containing renin inhibitory peptides. , 1987, Journal of medicinal chemistry.

[27]  Y. Kiso,et al.  Small-sized BACE1 inhibitors , 2006 .

[28]  Roland L. Dunbrack,et al.  Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase. , 2000, Journal of molecular biology.

[29]  E. Corey,et al.  Useful procedures for the oxidation of alcohols involving pyridinium dichromate in aprotic media , 1979 .