Novel S1P(1) receptor agonists--part 2: from bicyclo[3.1.0]hexane-fused thiophenes to isobutyl substituted thiophenes.
J Med Chem
; 57(1): 78-97, 2014 Jan 09.
Article
em En
| MEDLINE
| ID: mdl-24345087
Previously, we reported on the discovery of a novel series of bicyclo[3.1.0]hexane fused thiophene derivatives that serve as potent and selective S1P1 receptor agonists. Here, we discuss our efforts to simplify the bicyclohexane fused thiophene head. In a first step the bicyclohexane moiety could be replaced by a simpler, less rigid cyclohexane ring without compromising the S1P receptor affinity profile of these novel compounds. In a second step, the thiophene head was simplified even further by replacing the cyclohexane ring with an isobutyl group attached either to position 4 or position 5 of the thiophene. These structurally much simpler headgroups again furnished potent and selective S1P1 agonists (e.g., 87), which efficiently and dose dependently reduced the number of circulating lymphocytes upon oral administration to male Wistar rats. For several compounds discussed in this report lymphatic transport is an important route of absorption that may offer opportunities for a tissue targeted approach with minimal plasma exposure.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiofenos
/
Compostos Bicíclicos com Pontes
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Receptores de Lisoesfingolipídeo
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2014
Tipo de documento:
Article