Jeffrey Misiaszek | Stevens Institute of Technology (original) (raw)

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Papers by Jeffrey Misiaszek

Research paper thumbnail of Discovery of novel, potent BACE inhibitors with central activity for the treatment of Alzheimer's disease

Alzheimer's & Dementia, 2010

Research paper thumbnail of Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

ACS Medicinal Chemistry Letters, 2012

Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approa... more Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.

Research paper thumbnail of Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor

Bioorganic & Medicinal Chemistry Letters, 2012

Alzheimer 0 s disease Iminohydantoin In vivo a b s t r a c t From an initial lead 1, a structure-... more Alzheimer 0 s disease Iminohydantoin In vivo a b s t r a c t From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Ab following oral administration to rats. Herein we report SAR development in the S3 and F 0 subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.

Research paper thumbnail of Discovery of novel, potent BACE inhibitors with central activity for the treatment of Alzheimer's disease

Alzheimer's & Dementia, 2010

Research paper thumbnail of Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

ACS Medicinal Chemistry Letters, 2012

Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approa... more Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.

Research paper thumbnail of Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor

Bioorganic & Medicinal Chemistry Letters, 2012

Alzheimer 0 s disease Iminohydantoin In vivo a b s t r a c t From an initial lead 1, a structure-... more Alzheimer 0 s disease Iminohydantoin In vivo a b s t r a c t From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Ab following oral administration to rats. Herein we report SAR development in the S3 and F 0 subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.

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