Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): a gamma-secretase inhibitor with Abeta lowering activity in a transgenic mouse model of AD

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:

2007

Contact PI Name:

C. V.C. Prasad

Contact PI Affiliation:

Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut, USA

Co-Authors:

M. Zheng, S. Vig, C. Bergstrom, D.W. Smith, Q. Gao, S. Yeola, C.T. Polson, J.A. Corsa, V.L. Guss, A. Loo, J. Wang, B.G. Sleczka, C. Dangler, B.J. Robertson, J.P. Hendrick, S.B. Roberts, D.M. Barten

Primary Reference (PubMED ID):

17502137

Funding Source:

Not Reported

Study Goal and Principal Findings:

This report was on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.

Therapeutic Agent

Therapeutic Information:

Therapy Type:

Small Molecule

Therapeutic Agent:

BMS-433796

Therapeutic Target:

gamma Secretase

Open Targets

Pharos

Animal Model

Model Information:

Species:

Mouse

Model Type:

APP

Model Name:

Tg2576

ALZFORUM

Strain/Genetic Background:

Not Reported

Species:

Rat

Model Type:

Outbred

Model Name:

Sprague Dawley

Strain/Genetic Background:

Not Applicable

Experimental Design

Is the following information reported in the study?:

Power/Sample Size Calculation

Randomized into Groups

Blinded for Treatment

Blinded for Outcome Measures

Pharmacokinetic Measures

Pharmacodynamic Measures

Toxicology Measures

ADME Measures

Biomarkers

Dose

Formulation

Route of Delivery

Duration of Treatment

Frequency of Administration

Age of Animal at the Beginning of Treatment

Age of Animal at the End of Treatment

Sex as a Biological Variable

Study Balanced for Sex as a Biological Variable

Number of Premature Deaths

Number of Excluded Animals

Statistical Plan

Genetic Background

Inclusion/Exclusion Criteria Included

Conflict of Interest

Outcomes

Outcome Measured

Outcome Parameters

Biochemical

Brain-Buffer Soluble beta Amyloid Peptides

Notch Cleavage

ED50

IC50

Plasma-beta Amyloid Peptides

Brain-beta Amyloid Peptide-Total

Biomarker

Plasma-beta Amyloid Peptides

Pharmacokinetics

Drug Concentration-Brain

Drug Concentration-Plasma

Clearance (L/h/kg)

Oral Bioavailability (F%)

Metabolite Concentration-Brain

Metabolite Concentration-Plasma

Bioavailability

Pharmacodynamics

Target Engagement (Reduction beta Amyloid Peptides-Brain)

Target Engagement (Reduction beta Amyloid Peptides-Plasma)

Toxicology

Systemic Tissue Histotoxicity

Body Weight

Morbidity

Mortality

Physical Appearance

Notch-Mediated Toxicity

ADME

CYP450 Inhibition

Metabolic Stability

Drug Metabolites

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