Literature DB >> 26005540

Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability.

Martin Pettersson1, Douglas S Johnson1, John M Humphrey2, Todd W Butler2, Christopher W Am Ende2, Benjamin A Fish2, Michael E Green1, Gregory W Kauffman2, Patrick B Mullins2, Christopher J O'Donnell2, Antonia F Stepan1, Cory M Stiff2, Chakrapani Subramanyam2, Tuan P Tran2, Beth Cooper Vetelino2, Eddie Yang2, Longfei Xie2, Kelly R Bales1, Leslie R Pustilnik2, Stefanus J Steyn1, Kathleen M Wood1, Patrick R Verhoest1.   

Abstract

Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aβ42 and Aβ40 were observed in a guinea pig time-course experiment.

Entities:  

Keywords:  Alzheimer’s disease; LipMetE; fluorine; gamma secretase modulators; lipophilic metabolism efficiency

Year:  2015        PMID： 26005540      PMCID： PMC4434474          DOI： 10.1021/acsmedchemlett.5b00070

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


  30 in total

1.  Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active γ-secretase modulators.

Authors:  Martin Pettersson; Douglas S Johnson; Chakrapani Subramanyam; Kelly R Bales; Christopher W am Ende; Benjamin A Fish; Michael E Green; Gregory W Kauffman; Ricardo Lira; Patrick B Mullins; Thayalan Navaratnam; Subas M Sakya; Cory M Stiff; Tuan P Tran; Beth C Vetelino; Longfei Xie; Liming Zhang; Leslie R Pustilnik; Kathleen M Wood; Christopher J O'Donnell
Journal:  Bioorg Med Chem Lett       Date:  2012-03-01       Impact factor: 2.823

2.  Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties.

Authors:  Travis T Wager; Xinjun Hou; Patrick R Verhoest; Anabella Villalobos
Journal:  ACS Chem Neurosci       Date:  2010-03-25       Impact factor: 4.418

Review 3.  Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease.

Authors:  Bart De Strooper; Takeshi Iwatsubo; Michael S Wolfe
Journal:  Cold Spring Harb Perspect Med       Date:  2012-01       Impact factor: 6.915

4.  Evaluating the differences in cycloalkyl ether metabolism using the design parameter "lipophilic metabolism efficiency" (LipMetE) and a matched molecular pairs analysis.

Authors:  Antonia F Stepan; Gregory W Kauffman; Christopher E Keefer; Patrick R Verhoest; Martin Edwards
Journal:  J Med Chem       Date:  2013-08-21       Impact factor: 7.446

5.  A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes.

Authors:  Robert J Riley; D F McGinnity; R P Austin
Journal:  Drug Metab Dispos       Date:  2005-06-02       Impact factor: 3.922

6.  Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

Authors:  Vladimir Coric; Christopher H van Dyck; Stephen Salloway; Niels Andreasen; Mark Brody; Ralph W Richter; Hilkka Soininen; Stephen Thein; Thomas Shiovitz; Gary Pilcher; Susan Colby; Linda Rollin; Randy Dockens; Chahin Pachai; Erik Portelius; Ulf Andreasson; Kaj Blennow; Holly Soares; Charles Albright; Howard H Feldman; Robert M Berman
Journal:  Arch Neurol       Date:  2012-11

Review 7.  The many substrates of presenilin/γ-secretase.

Authors:  Annakaisa Haapasalo; Dora M Kovacs
Journal:  J Alzheimers Dis       Date:  2011       Impact factor: 4.472

8.  Synthesis of pyridopyrazine-1,6-diones from 6-hydroxypicolinic acids via a one-pot coupling/cyclization reaction.

Authors:  Tuan P Tran; Patrick B Mullins; Christopher W am Ende; Martin Pettersson
Journal:  Org Lett       Date:  2013-01-18       Impact factor: 6.005

9.  Escape from flatland: increasing saturation as an approach to improving clinical success.

Authors:  Frank Lovering; Jack Bikker; Christine Humblet
Journal:  J Med Chem       Date:  2009-11-12       Impact factor: 7.446

10.  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.

Authors:  Tanya Hay; Rhys Jones; Kevin Beaumont; Mark Kemp
Journal:  Drug Metab Dispos       Date:  2009-06-22       Impact factor: 3.922
View more
  5 in total

1.  Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators.

Authors:  Kevin D Rynearson; Ronald N Buckle; R Jason Herr; Nicholas J Mayhew; Xinchao Chen; William D Paquette; Samuel A Sakwa; Jinhai Yang; Keith D Barnes; Phuong Nguyen; William C Mobley; Graham Johnson; Juinn H Lin; Rudolph E Tanzi; Steven L Wagner
Journal:  Bioorg Med Chem       Date:  2020-09-01       Impact factor: 3.641

2.  Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half-life.

Authors:  Lei Liu; Bianca M Lauro; Li Ding; Matteo Rovere; Michael S Wolfe; Dennis J Selkoe
Journal:  Alzheimers Dement       Date:  2019-08-12       Impact factor: 21.566

3.  LipMetE (Lipophilic Metabolism Efficiency) as a Simple Guide for Half-Life and Dosing Regimen Prediction of Oral Drugs.

Authors:  Giuseppe Cecere; Laura Guasch; Andres M Olivares-Morales; Kenichi Umehara; Antonia F Stepan
Journal:  ACS Med Chem Lett       Date:  2022-08-23       Impact factor: 4.632

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

Authors:  Martin Pettersson; Douglas S Johnson; Danica A Rankic; Gregory W Kauffman; Christopher W Am Ende; Todd W Butler; Brian Boscoe; Edelweiss Evrard; Christopher J Helal; John M Humphrey; Antonia F Stepan; Cory M Stiff; Eddie Yang; Longfei Xie; Kelly R Bales; Eva Hajos-Korcsok; Stephen Jenkinson; Betty Pettersen; Leslie R Pustilnik; David S Ramirez; Stefanus J Steyn; Kathleen M Wood; Patrick R Verhoest
Journal:  Medchemcomm       Date:  2016-11-02       Impact factor: 3.597

Review 5.  Structural and Chemical Biology of Presenilin Complexes.

Authors:  Douglas S Johnson; Yue-Ming Li; Martin Pettersson; Peter H St George-Hyslop
Journal:  Cold Spring Harb Perspect Med       Date:  2017-12-01       Impact factor: 6.915
  5 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.