Abstract
We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.
MeSH terms
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2-Hydroxyphenethylamine / analogs & derivatives*
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2-Hydroxyphenethylamine / chemistry
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Administration, Oral
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Adrenergic Agonists / chemical synthesis*
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Adrenergic Agonists / chemistry
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Adrenergic Agonists / pharmacology*
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Adrenergic beta-3 Receptor Agonists*
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Animals
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Benzoic Acid / chemical synthesis*
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Benzoic Acid / chemistry
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Benzoic Acid / pharmacology*
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Biphenyl Compounds / chemistry*
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Boronic Acids / chemistry
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CHO Cells
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Cricetinae
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Cricetulus
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Dogs
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Epoxy Compounds / administration & dosage
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Epoxy Compounds / chemistry
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Ether / chemistry
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Humans
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Molecular Structure
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Receptors, Adrenergic, beta-3 / metabolism
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Structure-Activity Relationship
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Tetrahydronaphthalenes / chemistry*
Substances
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Adrenergic Agonists
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Adrenergic beta-3 Receptor Agonists
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Biphenyl Compounds
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Boronic Acids
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Epoxy Compounds
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Receptors, Adrenergic, beta-3
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Tetrahydronaphthalenes
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Ether
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2-Hydroxyphenethylamine
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Benzoic Acid