Jean-Simon Duceppe

LARGE SCALE PREPARATION OF (2S,3S)-N-BOC-3-AMINO-1,2-EPOXY-4-PHENYLBUTANE : A KEY BUILDING BLOCK FOR HIV-PROTEASE INHIBITORS

Abstract (2S,3S)-N-Boc-3-amino-1,2-epoxy-4-phenylbutane is prepared in four steps from commercially available N,N-dibenzyl-L-phenylalaninol. The synthesis is amenable to the preparation of kilogram quantities of enantiomerically pure material.

Preparation of enantiopure 4-oxygenated pipecolic acid derivatives

Abstract Two approaches to enantiopure 4-oxo- and 4-( R )-hydroxypipecolic acid derivatives from protected L-aspartic acid were developed. The first route exploits an intramolecular Michael addition on the stable enaminone 8 . Hydrogenation and concomitant decarboxylation gave the 4-oxo derivative 11 which was reduced selectively to the 4-( R )-hydroxy derivative 12 . The second route starts with a Michael addition followed by an intramolecular Dieckmann condensation to build the piperidine ring. The 4-oxo derivatives 11 and 19 are thus obtained in an expeditious manner on large scale without any chromatographic purification. Both sequences proved to be highly stereoselective.

2,4,6-Trisubstituted Triazines as Protein A Mimetics for the Treatment of Autoimmune Diseases

A first-in-class series of low molecular weight trisubstituted triazines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 1,3-phenylenediamine component was essential for robust activity. Twenty-two compounds, represented by lead molecule 34, displayed significant activity compared to protein A. These compounds may prove useful for the treatment of autoimmune disease.

Dimethylthiazolidine Carboxylic Acid as a Rigid P3 Unit in Inhibitors of Serine Proteases: Application to Two Targets†

Serine proteases are a very large class of enzymes, many of which represent important targets for therapeutic agents against a wide variety of disease states. The similarity in active site architecture for these proteases has often allowed inhibitor design strategies for a particular target to be successfully applied to other enzymes in the class. In many cases, the presence of a bulky P3 amino acid residue in peptide‐based inhibitors is central to conferring an extended peptide conformation, critical to binding of the ligands to serine protease active sites. The dimethylthiazolidine carboxylic acid ‘residue’ was found to be effective as a novel P3 replacement in peptidomimetic inhibitors of two distinct serine proteases, the hepatitis C NS3 protease and the human cytomegalovirus maturational protease. An array of NMR methods was used to confirm that the dimethylthiazolidine carboxylic acid unit indeed confers conformational and dynamic properties very similar to that of the rigidified parent structures.

Design and Synthesis of New 1,3,5-Trisubstituted Triazines for the Treatment of Cancer and Inflammation

Abstract Low‐molecular‐weight synthetic molecules 1 with the general 2‐(fluorophenylamino)‐4,6‐disubstituted 1,3,5‐triazine structure and showing anti‐inflammatory and anticancer activities were explored. Structure–activity relationship studies demonstrated the importance of the aminopentyl chain, the 3‐ or 4‐fluorophenylaniline component, and the presence of at least one substituent, such as a tyramine moiety, attached directly to the triazine ring as essential for good activity. These compounds, represented by leads 4‐{2‐[4‐(5‐Aminopentylamino)‐6‐(3‐fluorophenylamino)‐1,3,5‐triazin‐2‐ylamino]ethyl}phenol (6) and 4‐{2‐[4‐(5‐Aminopentylamino)‐6‐(4‐fluorophenylamino)‐1,3,5‐triazin‐2‐ylamino]ethyl}phenol (10), displayed moderate and significant in vitro and in vivo dual activities, respectively, and address the molecular link between inflammation and cancer. Compound 10 demonstrated significant antitumor efficacy upon administration by the oral and intravenous routes in several animal models. This class of triazine compounds is new, safe, and nontoxic and offers a novel approach to the treatment of inflammation and cancer.

P126 Oral treatment with PBI-4050 ameliorates bleomycin-induced pulmonary fibrosis by reducing serum and lung anti-inflammatory/fibrotic biomarkers.

PBI-4050 is a first-in-class orally active compound which displays antifibrotic activities in kidney, heart, liver, pancreas and lung models. PBI-4050 was found to be safe and well tolerated in healthy volunteers and in patients with CKD and Type 2 diabetes without any SAEs. Translation of pharmacological efficacy in humans …