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Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2006 Dec 15; Vol. 16 (24), pp. 6165-9. Date of Electronic Publication: 2006 Oct 05. - Publication Year :
- 2006
-
Abstract
- A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (K(i)=21nM) with good oral bioavailability in three species.
- Subjects :
- Administration, Oral
Benzimidazoles chemistry
Benzimidazoles pharmacokinetics
Benzimidazoles pharmacology
Biological Availability
Cell Line
Humans
Hydantoins chemistry
Kidney
Models, Molecular
Molecular Structure
Spiro Compounds chemistry
Structure-Activity Relationship
Calcitonin Gene-Related Peptide Receptor Antagonists
Hydantoins pharmacokinetics
Hydantoins pharmacology
Spiro Compounds pharmacokinetics
Spiro Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0960-894X
- Volume :
- 16
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 17027263
- Full Text :
- https://doi.org/10.1016/j.bmcl.2006.09.045