Conformational restriction approach to β-secretase (BACE1) inhibitors III: effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations.

For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ∼0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.

[1]  J. Ellman,et al.  Asymmetric synthesis of beta-amino acid derivatives incorporating a broad range of substitution patterns by enolate additions to tert-butanesulfinyl imines. , 2002, The Journal of organic chemistry.

[2]  S. Shuto,et al.  Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure. , 2003, Journal of medicinal chemistry.

[3]  J. Tang,et al.  Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  William Greenlee,et al.  Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation. , 2012, Journal of medicinal chemistry.

[5]  D. Hoffman,et al.  trans-1-[(2-Phenylcyclopropyl)methyl]-4-arylpiperazines: mixed dopamine D(2)/D(4) receptor antagonists as potential antipsychotic agents. , 2000, Journal of medicinal chemistry.

[6]  Y. Shitaka,et al.  [Progress in the development of anti-amyloid drugs for treatment of Alzheimer's disease.]. , 2010, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.

[7]  S. Gandy,et al.  The role of cerebral amyloid β accumulation in common forms of Alzheimer disease , 2005 .

[8]  N. Meanwell.  Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. , 2011, Chemical research in toxicology.

[9]  S. Eketjäll,et al.  New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain. , 2012, Journal of medicinal chemistry.

[10]  S. Shuto,et al.  Conformational analysis of the NMDA receptor antagonist (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) designed by a novel conformational restriction method based on the structural feature of cyclopropane ring. , 2002, Chemical & pharmaceutical bulletin.

[11]  R. Barbour,et al.  Purification and cloning of amyloid precursor protein β-secretase from human brain , 1999, Nature.

[12]  J. Treanor,et al.  Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. , 1999, Science.

[13]  F. Panza,et al.  Towards Disease-Modifying Treatment of Alzheimers Disease: Drugs Targeting β -Amyloid , 2009 .

[14]  S. Shuto,et al.  Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine. , 2002, The Journal of organic chemistry.

[15]  Jennifer Venhorst,et al.  Target-drug interactions: first principles and their application to drug discovery. , 2012, Drug discovery today.

[16]  I. Lieberburg,et al.  Cellular mechanisms of beta-amyloid production and secretion. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Conformational restriction approach to BACE1 inhibitors II: SAR study of the isocytosine derivatives fixed with a cis-cyclopropane ring. , 2013, Bioorganic & medicinal chemistry letters.

[18]  György G Ferenczy,et al.  Thermodynamics guided lead discovery and optimization. , 2010, Drug discovery today.

[19]  M. Faul,et al.  Reversal of diastereofacial selectivity in hydride reductions of N-tert-butanesulfinyl imines. , 2006, The Journal of organic chemistry.

[20]  Arun K. Ghosh,et al.  Developing β‐secretase inhibitors for treatment of Alzheimer’s disease , 2012, Journal of neurochemistry.

[21]  J. Ellman,et al.  Synthesis of Enantiomerically Pure N-tert-Butanesulfinyl Imines (tert-Butanesulfinimines) by the Direct Condensation of tert-Butanesulfinamide with Aldehydes and Ketones , 1999 .

[22]  James E Audia,et al.  Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor , 2011, The Journal of Neuroscience.

[23]  D. G. Udugamasooriya,et al.  Conformational constraint in protein ligand design and the inconsistency of binding entropy. , 2008, Biopolymers.

[24]  Ying-zi Xu,et al.  Small-molecule BACE1 inhibitors: a patent literature review (2006 – 2011) , 2012, Expert opinion on therapeutic patents.

[25]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[26]  T. Hirokawa,et al.  Investigation of the bioactive conformation of histamine H3 receptor antagonists by the cyclopropylic strain-based conformational restriction strategy. , 2010, Journal of medicinal chemistry.

[27]  A. Ganesan,et al.  Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors. , 2011, Bioorganic & medicinal chemistry.

[28]  S. Shuto,et al.  Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H3 and/or H4 receptor antagonists with an imidazolylcyclopropane structure. , 2006, Journal of medicinal chemistry.

[29]  Rajiv Chopra,et al.  Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors. , 2010, Journal of medicinal chemistry.

[30]  Gianni Chessari,et al.  Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency. , 2007, Journal of medicinal chemistry.

[31]  S. Tzeng,et al.  Protein activity regulation by conformational entropy , 2012, Nature.

[32]  S. Martin,et al.  Ligand preorganization may be accompanied by entropic penalties in protein-ligand interactions. , 2006, Angewandte Chemie.

[33]  Stephen F Martin,et al.  Thermodynamic and structural effects of conformational constraints in protein-ligand interactions. Entropic paradoxy associated with ligand preorganization. , 2009, Journal of the American Chemical Society.

[34]  R. Wahl,et al.  Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimer's disease. , 2012, Journal of medicinal chemistry.

[35]  T. Hirokawa,et al.  Cyclopropane-based stereochemical diversity-oriented conformational restriction strategy: histamine H3 and/or H4 receptor ligands with the 2,3-methanobutane backbone. , 2012, Organic & biomolecular chemistry.

[36]  M. Ohno,et al.  BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease , 2004, Neuron.

[37]  Alfredo G. Tomasselli,et al.  Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity , 1999, Nature.

[38]  S. Shuto,et al.  Construction of a cis-cyclopropane via reductive radical decarboxylation. Enantioselective synthesis of cis- and trans-1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents. , 2003, The Journal of organic chemistry.

[39]  S. Shuto,et al.  Conformational restriction approach to β-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode. , 2012, Journal of medicinal chemistry.

[40]  M. James,et al.  Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes. , 1998, Biochemistry.

[41]  J. Ellman,et al.  The tert-Butanesulfinyl Group: An Ideal Chiral Directing Group and Boc-Surrogate for the Asymmetric Synthesis and Applications of beta-Amino Acids. , 1999, The Journal of organic chemistry.

[42]  J. H. Clements,et al.  Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions. , 2010, ACS medicinal chemistry letters.

[43]  Britt-Marie Swahn,et al.  Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. , 2012, Journal of medicinal chemistry.

[44]  G. Varchi,et al.  The first synthesis of N,O-protected β2,2,3,3-isoserines bearing two adjacent quaternary stereogenic centers and their corresponding β-lactams , 2007 .

[45]  Gabriel Waksman,et al.  Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide inhibitors of Src SH2 domain binding. , 2002, Journal of the American Chemical Society.

[46]  Suresh Babu,et al.  Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction. , 2012, ACS medicinal chemistry letters.

[47]  S. Shuto,et al.  Synthesis and biological activity of conformationally restricted analogs of milnacipran: (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxami de, an efficient noncompetitive N-methyl-D-aspartic acid receptor antagonist. , 1996, Journal of medicinal chemistry.

[48]  Britt-Marie Swahn,et al.  Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease* , 2012, The Journal of Biological Chemistry.

[49]  Matthew S. Johnson,et al.  Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors. , 2009, Journal of medicinal chemistry.

[50]  Matthew S. Johnson,et al.  Di-substituted pyridinyl aminohydantoins as potent and highly selective human beta-secretase (BACE1) inhibitors. , 2010, Bioorganic & medicinal chemistry.

[51]  S. Shuto,et al.  Conformational Restriction by Repulsion between Adjacent Substituents on a Cyclopropane Ring: Design and Enantioselective Synthesis of 1-Phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as Potent NMDA Receptor Antagonists , 1996 .

[52]  Gerhard Klebe,et al.  Adding calorimetric data to decision making in lead discovery: a hot tip , 2010, Nature Reviews Drug Discovery.

[53]  Dudley H. Williams,et al.  The free energy change of restricting a bond rotation in the binding of peptide analogues to vancomycin group antibiotics , 1993 .