A new rational hypothesis for the pharmacophore of the active metabolite of leflunomide, a potent immunosuppressive drug

Leflunomide is one of the most promising disease-modifying antirheumatic drug now in clinical trials for the treatment of rheumatoid arthritis. Metabolic studies have indicated that leflunomide is rapidly processed in vivo to an active metabolite, A771726 (2). To identify the chemical characteristics necessary for the immunosuppressive activity of 2, configurational and conformational studies were carried out on the latter and its inactive analogues (ethyl 3-hydroxy-2-((4-(trifluoromethyl)phenyl)carbamoyl)but-2-enoate, 3a, and 3-hydroxy-2-nitro-N-(4-(trifluoromethyl)phenyl)but-2-enamide, 3b). These studies suggested that the pharmacophore responsible for the immunosuppressive activity of 2 is a beta-keto amide with the enolic hydroxy group cis to the amidic moiety. To verify this hypothesis, a new class of immunosuppressive agents was designed and synthesized. Their testing in vitro and in vivo identified compounds which were more potent than both leflunomide and 2 and above all confirmed our hypothesis as to the key structural and chemical determinants for the immunosuppressive properties of 2 and our compounds.

Medienart:

Artikel

Erscheinungsjahr:

1997

Erschienen:

1997

Enthalten in:

Zur Gesamtaufnahme - volume:40

Enthalten in:

Journal of medicinal chemistry - 40(1997), 13 vom: 20. Juni, Seite 2011-6

Sprache:

Englisch

Beteiligte Personen:

Bertolini, G [VerfasserIn]
Aquino, M [VerfasserIn]
Biffi, M [VerfasserIn]
d'Atri, G [VerfasserIn]
Di Pierro, F [VerfasserIn]
Ferrario, F [VerfasserIn]
Mascagni, P [VerfasserIn]
Somenzi, F [VerfasserIn]
Zaliani, A [VerfasserIn]
Leoni, F [VerfasserIn]

Themen:

1C058IKG3B
Aniline Compounds
Crotonates
G162GK9U4W
Hydroxybutyrates
Immunosuppressive Agents
Isoxazoles
Journal Article
Leflunomide
Nitriles
Prodrugs
Teriflunomide
Toluidines

Anmerkungen:

Date Completed 07.08.1997

Date Revised 03.12.2021

published: Print

Citation Status MEDLINE

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM091626927