Journal article
Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy† †Electronic supplementary information (ESI) available. CCDC 1452774. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6md00406g
MedChemComm, Vol.8(4), pp.730-743
11/02/2016
Handle:
https://hdl.handle.net/2376/114597
PMCID: PMC6071960
PMID: 30108792
Abstract
γ-Secretase modulators for the treatment of Alzheimer's disease.
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.
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Details
- Title
- Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy† †Electronic supplementary information (ESI) available. CCDC 1452774. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6md00406g
- Creators
- Martin Pettersson - Neuroscience and Pain Medicinal Chemistry , Cambridge , Massachusetts 02139 , USA . EmailDouglas S Johnson - Neuroscience and Pain Medicinal Chemistry , Cambridge , Massachusetts 02139 , USA . EmailDanica A Rankic - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailGregory W Kauffman - Neuroscience and Pain Medicinal Chemistry , Cambridge , Massachusetts 02139 , USA . EmailChristopher W am Ende - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailTodd W Butler - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailBrian Boscoe - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailEdelweiss Evrard - Neuroscience and Pain Medicinal Chemistry , Cambridge , Massachusetts 02139 , USA . EmailChristopher J Helal - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailJohn M Humphrey - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailAntonia F Stepan - Neuroscience and Pain Medicinal Chemistry , Cambridge , Massachusetts 02139 , USA . EmailCory M Stiff - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailEddie Yang - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailLongfei Xie - Neuroscience and Pain Medicinal Chemistry , Groton , Connecticut 06340 , USA . EmailKelly R Bales - Neuroscience and Pain Research Unit , Cambridge , Massachusetts 02139 , USAEva Hajos-Korcsok - Neuroscience and Pain Research Unit , Cambridge , Massachusetts 02139 , USAStephen Jenkinson - Global Safety Pharmacology , Pfizer Worldwide Research and Development , La Jolla , California 92121 , USABetty Pettersen - Drug Safety R&D , Pfizer Worldwide Research and Development , Groton , Connecticut 06340 , USALeslie R Pustilnik - Primary Pharmacology Group , Groton , Connecticut 06340 , USADavid S Ramirez - Global Safety Pharmacology , Pfizer Worldwide Research and Development , La Jolla , California 92121 , USAStefanus J Steyn - Pharmacokinetics, Dynamics and Metabolism , Pfizer Worldwide Research and Development , Cambridge , Massachusetts 02139 , USAKathleen M Wood - Neuroscience and Pain Research Unit , Cambridge , Massachusetts 02139 , USAPatrick R Verhoest - Neuroscience and Pain Medicinal Chemistry , Cambridge , Massachusetts 02139 , USA . Email
- Publication Details
- MedChemComm, Vol.8(4), pp.730-743
- Publisher
- Royal Society of Chemistry
- Identifiers
- 99900547531401842
- Language
- English
- Resource Type
- Journal article