Abstract
As part of our research for novel calcium-sensing receptor (CaSR) antagonists that can function as oral bone anabolic agents, we recently reported the discovery of a tetrahydropyrazolopyrimidine derivative featuring adamantyl group 1b with potent CaSR antagonistic activity. To explore the potential of this calcilytic congener, we introduced the gem-dialkyl benzyl group at the 3-position of the tetrahydropyrazolopyrimidine ring, forming a bioisostere of the adamantyl group by mimicking the adamantyl group's lipophilicity and bulkiness. Optimization directed toward the improvement of solubility and metabolic stability led to the discovery of compound 9e, which stimulated transient PTH secretion when orally administered to normal rats. Further, compound 9e proved to be fully effective in an osteopenic ovariectomized rat model.
MeSH terms
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Administration, Oral
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Animals
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Bone Density / drug effects
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Bone Density Conservation Agents / chemical synthesis*
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Bone Density Conservation Agents / pharmacokinetics
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Bone Density Conservation Agents / pharmacology
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Bone Diseases, Metabolic / drug therapy
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Bone Diseases, Metabolic / physiopathology
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CHO Cells
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Caco-2 Cells
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Cell Membrane Permeability
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Cricetinae
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Cricetulus
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Crystallography, X-Ray
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Humans
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Molecular Structure
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Osteocalcin / blood
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Ovariectomy
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Parathyroid Hormone / metabolism*
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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Receptors, Calcium-Sensing / antagonists & inhibitors*
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Bone Density Conservation Agents
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N-(1-ethyl-1-(4-methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo(1,5-a)pyrimidine-3-carboxamide
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Parathyroid Hormone
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Pyrazoles
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Pyrimidines
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Receptors, Calcium-Sensing
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Osteocalcin