Abstract
Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Hedgehog Proteins / antagonists & inhibitors*
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Hedgehog Proteins / metabolism
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Humans
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Mice
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Microsomes, Liver / metabolism
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Phthalazines / chemical synthesis
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Phthalazines / chemistry*
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Phthalazines / pharmacokinetics
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Piperazines / chemical synthesis
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Piperazines / chemistry*
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Piperazines / pharmacokinetics
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Pregnane X Receptor
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Pyridazines / chemical synthesis
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Pyridazines / chemistry*
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Pyridazines / pharmacokinetics
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Rats
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / metabolism
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Receptors, Steroid / chemistry*
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Receptors, Steroid / metabolism
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Signal Transduction
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Smoothened Receptor
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Structure-Activity Relationship
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Tylosin / analogs & derivatives
Substances
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4-'demycarosyl-20-deoxo-20-(di-N-benzylamino)-8a-aza-8a-homotylosin
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4-(4-phenylphthalazine-1-yl)piperazine amide
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Hedgehog Proteins
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Phthalazines
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Piperazines
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Pregnane X Receptor
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Pyridazines
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Receptors, G-Protein-Coupled
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Receptors, Steroid
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SMO protein, human
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Smoothened Receptor
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pyridazine
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phthalazine
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Tylosin