Hubert B. Josien

Studies to Investigate the in Vivo Therapeutic Window of the γ-Secretase Inhibitor N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) in the CRND8 Mouse

Accumulation of amyloid β-peptide (Aβ) is considered a key step in the etiology of Alzheimers disease. Aβ is produced by sequential cleavage of the amyloid precursor protein by β- and γ-secretase enzymes. Consequently, inhibition of γ-secretase provides a promising therapeutic approach to treat Alzheimers disease. Preclinically, several γ-secretase inhibitors have been shown to reduce plasma and brain Aβ, although they also produce mechanism-based side effects, including thymus atrophy and intestinal goblet cell hyperplasia. The present studies sought to establish an efficient screen for determining the therapeutic window of γ-secretase inhibitors and to test various means of maximizing this window. Six-day oral administration of the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) reduced cortical Aβ40 in young (preplaque) transgenic CRND8 mice (ED50 ≈ 0.6 mg/kg) and produced significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window was similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects were reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411,575 reduced cortical Aβ40 by 69% without inducing intestinal effects, although a previously unreported change in coat color was observed. These studies demonstrate that the 3- to 5-fold therapeutic window for LY411,575 can be exploited to obtain reduction in Aβ levels without induction of intestinal side effects, that intermittent treatment could be used to mitigate side effects, and that a 6-day dosing paradigm can be used to rapidly determine the therapeutic window of novel γ-secretase inhibitors.

Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

Novel orally active morpholine N-arylsulfonamides γ-secretase inhibitors with low CYP 3A4 liability

A new class of 2,6-disubstituted morpholine N-arylsulfonamide gamma-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Abeta levels in Tg CRND8 mice upon oral administration were identified.