Abstract
Our efforts to discover potent, orally bioavailable type II calcimimetic agents for the treatment of secondary hyperparathyroidism focused on the development of ring constrained analogues of the known calcimimetic R-568. The structure-activity relationships of various substituted heterocycles and their effects on the human calcium-sensing receptor are discussed. Pyrazole 15 was shown to be efficacious in a rat in vivo pharmacodynamic model.
MeSH terms
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Administration, Oral
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Animals
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Biological Availability
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Cell Line
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Crystallography, X-Ray
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Humans
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Hyperparathyroidism, Secondary / drug therapy
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Male
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Methylamines / chemical synthesis*
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Methylamines / chemistry
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Methylamines / pharmacology
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Molecular Structure
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Parathyroid Hormone / blood
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Phenethylamines
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Propylamines
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Calcium-Sensing / agonists*
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Receptors, Calcium-Sensing / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Aniline Compounds
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Methylamines
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N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
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Parathyroid Hormone
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Phenethylamines
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Propylamines
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Pyrazoles
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Receptors, Calcium-Sensing