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Novel S1P(1) receptor agonists--part 2: from bicyclo[3.1.0]hexane-fused thiophenes to isobutyl substituted thiophenes
- Source :
- Journal of medicinal chemistry. 57(1)
- Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Male
Bicyclic molecule
Cyclohexane
S1p1 receptor
Stereochemistry
Thiophenes
Ring (chemistry)
Thiophene derivatives
Rats
Hexane
chemistry.chemical_compound
Bridged Bicyclo Compounds
Receptors, Lysosphingolipid
Structure-Activity Relationship
chemistry
Drug Discovery
Thiophene
Molecular Medicine
Moiety
Animals
Humans
Rats, Wistar
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 57
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....06de7a43cbf3545aeddc6cc6f7e65b53