Literature DB >> 31413800

Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.

Daniel Oehlrich1, Aldo Peschiulli1, Gary Tresadern1, Michiel Van Gool2, Juan Antonio Vega2, Ana Isabel De Lucas2, Sergio A Alonso de Diego2, Hana Prokopcova1, Nigel Austin1, Sven Van Brandt1, Michel Surkyn1, Michel De Cleyn1, Ann Vos1, Frederik J R Rombouts1, Gregor Macdonald1, Dieder Moechars1, Harrie J M Gijsen1, Andrés A Trabanco2.   

Abstract

Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.

Entities:  

Year:  2019        PMID： 31413800      PMCID： PMC6691570          DOI： 10.1021/acsmedchemlett.9b00181

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  14 in total

1.  Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors.

Authors:  Gary Tresadern; Francisca Delgado; Oscar Delgado; Harrie Gijsen; Gregor J Macdonald; Dieder Moechars; Frederik Rombouts; Richard Alexander; John Spurlino; Michiel Van Gool; Juan Antonio Vega; Andrés A Trabanco
Journal:  Bioorg Med Chem Lett       Date:  2011-10-20       Impact factor: 2.823

2.  Purification and cloning of amyloid precursor protein beta-secretase from human brain.

Authors:  S Sinha; J P Anderson; R Barbour; G S Basi; R Caccavello; D Davis; M Doan; H F Dovey; N Frigon; J Hong; K Jacobson-Croak; N Jewett; P Keim; J Knops; I Lieberburg; M Power; H Tan; G Tatsuno; J Tung; D Schenk; P Seubert; S M Suomensaari; S Wang; D Walker; J Zhao; L McConlogue; V John
Journal:  Nature       Date:  1999-12-02       Impact factor: 49.962

Review 3.  Alzheimer's disease: the amyloid cascade hypothesis.

Authors:  J A Hardy; G A Higgins
Journal:  Science       Date:  1992-04-10       Impact factor: 47.728

4.  β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease.

Authors:  Hans Hilpert; Wolfgang Guba; Thomas J Woltering; Wolfgang Wostl; Emmanuel Pinard; Harald Mauser; Alexander V Mayweg; Mark Rogers-Evans; Roland Humm; Daniela Krummenacher; Thorsten Muser; Christian Schnider; Helmut Jacobsen; Laurence Ozmen; Alessandra Bergadano; David W Banner; Remo Hochstrasser; Andreas Kuglstatter; Pascale David-Pierson; Holger Fischer; Alessandra Polara; Robert Narquizian
Journal:  J Med Chem       Date:  2013-05-02       Impact factor: 7.446

5.  Application of Free Energy Perturbation for the Design of BACE1 Inhibitors.

Authors:  Myriam Ciordia; Laura Pérez-Benito; Francisca Delgado; Andrés A Trabanco; Gary Tresadern
Journal:  J Chem Inf Model       Date:  2016-08-24       Impact factor: 4.956

6.  1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.

Authors:  Frederik J R Rombouts; Gary Tresadern; Oscar Delgado; Carolina Martínez-Lamenca; Michiel Van Gool; Aránzazu García-Molina; Sergio A Alonso de Diego; Daniel Oehlrich; Hana Prokopcova; José Manuel Alonso; Nigel Austin; Herman Borghys; Sven Van Brandt; Michel Surkyn; Michel De Cleyn; Ann Vos; Richard Alexander; Gregor Macdonald; Dieder Moechars; Harrie Gijsen; Andrés A Trabanco
Journal:  J Med Chem       Date:  2015-10-10       Impact factor: 7.446

7.  N-heterocycle construction via cyclic sulfamidates. Applications in synthesis.

Authors:  John F Bower; Janjira Rujirawanich; Timothy Gallagher
Journal:  Org Biomol Chem       Date:  2010-01-28       Impact factor: 3.876

8.  Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase.

Authors:  J T Huse; D S Pijak; G J Leslie; V M Lee; R W Doms
Journal:  J Biol Chem       Date:  2000-10-27       Impact factor: 5.157

9.  2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.

Authors:  Ellen W Baxter; Kelly A Conway; Ludo Kennis; François Bischoff; Marc H Mercken; Hans L De Winter; Charles H Reynolds; Brett A Tounge; Chi Luo; Malcolm K Scott; Yifang Huang; Mirielle Braeken; Serge M A Pieters; Didier J C Berthelot; Stefan Masure; Wouter D Bruinzeel; Alfonzo D Jordan; Michael H Parker; Robert E Boyd; Junya Qu; Richard S Alexander; Douglas E Brenneman; Allen B Reitz
Journal:  J Med Chem       Date:  2007-08-08       Impact factor: 7.446

Review 10.  The evolution of amidine-based brain penetrant BACE1 inhibitors.

Authors:  Daniel Oehlrich; Hana Prokopcova; Harrie J M Gijsen
Journal:  Bioorg Med Chem Lett       Date:  2014-03-20       Impact factor: 2.823
View more
  2 in total

1.  A Brain-Penetrant and Bioavailable Pyrazolopiperazine BACE1 Inhibitor Elicits Sustained Reduction of Amyloid β In Vivo.

Authors:  Aldo Peschiulli; Daniel Oehlrich; Michiel Van Gool; Nigel Austin; Sven Van Brandt; Michel Surkyn; Michel De Cleyn; Ann Vos; Gary Tresadern; Frederik J R Rombouts; Gregor J Macdonald; Diederik Moechars; Andrés A Trabanco; Harrie J M Gijsen
Journal:  ACS Med Chem Lett       Date:  2021-12-01       Impact factor: 4.345

Review 2.  Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines and Pyridazines.

Authors:  Gavin R Hoffman; Allen M Schoffstall
Journal:  Molecules       Date:  2022-07-22       Impact factor: 4.927
  2 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.