Emmanuel Demont

Second Generation of Hydroxyethylamine Bace-1 Inhibitors: Optimizing Potency and Oral Bioavailability.

BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimers disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.

Bace-1 Inhibitors Part 2: Identification of Hydroxy Ethylamines (Heas) with Reduced Peptidic Character.

This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)() and P(2)() substituents, two different binding modes were observed in X-ray co-crystal structures.

Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics

Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.

Bace-1 Inhibitors Part 3: Identification of Hydroxy Ethylamines (Heas) with Nanomolar Potency in Cells.

This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.

Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimers disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.

BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs).

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimers disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.

Second Generation of Bace-1 Inhibitors Part 2: Optimisation of the Non-Prime Side Substituent.

Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimers disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.

Synthesis of (-)-swainsonine and (-)-8-epi-swainsonine by the addition of allenylmetals to chiral α,β-alkoxy sulfinylimines.

The asymmetric synthesis of (-)-swainsonine and (-)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure α,β-dialkoxy N-tert-butanesulfinylimines derived from d-erythronolactone.

A Chemical Probe for the ATAD2 Bromodomain.

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.

Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1 and S1P5 Receptors Efficacious at Low Oral Dose

2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RRMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P(5) agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (<1 mg p.o. once daily).