Abstract
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
MeSH terms
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Animals
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Blood-Brain Barrier / metabolism
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Brain / metabolism
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Capillary Permeability / drug effects
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Electrocardiography / drug effects
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Guinea Pigs
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Half-Life
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Histamine H1 Antagonists / chemical synthesis*
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Histamine H1 Antagonists / pharmacology
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Histamine H1 Antagonists / toxicity
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Humans
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / pharmacology
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Indoles / toxicity
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Male
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Mice
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Piperidines / chemical synthesis*
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Piperidines / pharmacology
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Piperidines / toxicity
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Radioligand Assay
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Rats
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Rats, Wistar
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Receptors, Adrenergic, alpha-1 / drug effects
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Receptors, Adrenergic, alpha-1 / metabolism
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Receptors, Histamine H1 / drug effects
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Receptors, Histamine H1 / metabolism
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Receptors, Serotonin / drug effects
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Receptors, Serotonin / metabolism
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Skin / blood supply
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Structure-Activity Relationship
Substances
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Cytochrome P-450 Enzyme Inhibitors
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Histamine H1 Antagonists
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Indoles
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Piperidines
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Receptors, Adrenergic, alpha-1
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Receptors, Histamine H1
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Receptors, Serotonin
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CYP3A protein, human
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Cytochrome P-450 CYP3A