Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy.

Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg-1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.

[1]  Gregory W. Kauffman,et al.  Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability. , 2015, ACS medicinal chemistry letters.

[2]  Gregory W. Kauffman,et al.  Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin. , 2015, Bioorganic & medicinal chemistry letters.

[3]  B. Strooper,et al.  Lessons from a Failed γ-Secretase Alzheimer Trial , 2014, Cell.

[4]  R. Pratap,et al.  Natural and synthetic chromenes, fused chromenes, and versatility of dihydrobenzo[h]chromenes in organic synthesis. , 2014, Chemical reviews.

[5]  Gregory W. Kauffman,et al.  Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators. , 2014, Journal of medicinal chemistry.

[6]  M. Jiang,et al.  Synthesis of 2,2‐Difluoro‐2H‐chromenes Through the Tandem Reaction of Ethyl 3‐Bromo‐3,3‐difluoropropionate with Salicylaldehyde Derivatives. , 2013 .

[7]  Gregory W. Kauffman,et al.  Novel γ-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012 , 2013, Expert opinion on therapeutic patents.

[8]  Gregory W. Kauffman,et al.  Evaluating the differences in cycloalkyl ether metabolism using the design parameter "lipophilic metabolism efficiency" (LipMetE) and a matched molecular pairs analysis. , 2013, Journal of medicinal chemistry.

[9]  Douglas S. Johnson,et al.  Development and mechanism of γ-secretase modulators for Alzheimer's disease. , 2013, Biochemistry.

[10]  W. Thies,et al.  2013 Alzheimer's disease facts and figures , 2013, Alzheimer's & Dementia.

[11]  K. Bales,et al.  γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin* , 2013, The Journal of Biological Chemistry.

[12]  Christopher W. am Ende,et al.  Synthesis of pyridopyrazine-1,6-diones from 6-hydroxypicolinic acids via a one-pot coupling/cyclization reaction. , 2013, Organic letters.

[13]  M. Mercken,et al.  γ-Secretase Modulators: Can We Combine Potency with Safety? , 2012, International journal of Alzheimer's disease.

[14]  K. Blennow,et al.  Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. , 2012, Archives of neurology.

[15]  Gregory W. Kauffman,et al.  Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active γ-secretase modulators. , 2012, Bioorganic & medicinal chemistry letters.

[16]  L. Pustilnik,et al.  Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors. , 2011, Journal of medicinal chemistry.

[17]  E. Corey,et al.  Selective formation of six-membered oxa- and carbocycles by the In(III)-activated ring closure of acetylenic substrates. , 2011, Organic letters.

[18]  B. Strooper,et al.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics , 2011, Nature Reviews Drug Discovery.

[19]  G. Kay,et al.  A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. , 2011, British journal of clinical pharmacology.

[20]  Xulun Zhang,et al.  Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease , 2010, Neuron.

[21]  P. Verhoest,et al.  Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. , 2010, ACS chemical neuroscience.

[22]  Alex C. Bissember,et al.  The Au(I)-catalyzed intramolecular hydroarylation of terminal alkynes under mild conditions: application to the synthesis of 2H-chromenes, coumarins, benzofurans, and dihydroquinolines. , 2009, The Journal of organic chemistry.

[23]  Tanya L Hay,et al.  Modulation of the Partition Coefficient between Octanol and Buffer at pH 7.4 and pKa to Achieve the Optimum Balance of Blood Clearance and Volume of Distribution for a Series of Tetrahydropyran Histamine Type 3 Receptor Antagonists , 2009, Drug Metabolism and Disposition.

[24]  Dafydd R Owen,et al.  Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis. , 2009, Bioorganic & medicinal chemistry letters.

[25]  D. Teplow,et al.  Amyloid beta protein: Abeta40 inhibits Abeta42 oligomerization. , 2009, Journal of the American Chemical Society.

[26]  Bo Feng,et al.  In Vitro P-glycoprotein Assays to Predict the in Vivo Interactions of P-glycoprotein with Drugs in the Central Nervous System , 2008, Drug Metabolism and Disposition.

[27]  R. Schulz,et al.  Isolated heart perfusion according to Langendorff---still viable in the new millennium. , 2007, Journal of pharmacological and toxicological methods.

[28]  R. Austin,et al.  A UNIFIED MODEL FOR PREDICTING HUMAN HEPATIC, METABOLIC CLEARANCE FROM IN VITRO INTRINSIC CLEARANCE DATA IN HEPATOCYTES AND MICROSOMES , 2005, Drug Metabolism and Disposition.

[29]  Margit Asmild,et al.  Characterization of potassium channel modulators with QPatch automated patch-clamp technology: system characteristics and performance. , 2003, Assay and drug development technologies.

[30]  Rong Wang,et al.  A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity , 2001, Nature.

[31]  R. Obach,et al.  Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[32]  A. Hall,et al.  γ-Secretase modulators: current status and future directions. , 2014, Progress in medicinal chemistry.

[33]  B. de Strooper,et al.  Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease. , 2012, Cold Spring Harbor perspectives in medicine.