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.
MeSH terms
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Administration, Oral
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Biological Availability
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Calcitonin Gene-Related Peptide Receptor Antagonists*
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Cell Line
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Humans
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Hydantoins / chemistry
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Hydantoins / pharmacokinetics*
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Hydantoins / pharmacology*
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Kidney
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Models, Molecular
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Molecular Structure
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacokinetics*
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
Substances
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Benzimidazoles
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Calcitonin Gene-Related Peptide Receptor Antagonists
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Hydantoins
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Spiro Compounds