Abstract
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.
MeSH terms
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Animals
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Cells, Cultured
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Chemical Phenomena
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Chemistry, Physical
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DNA, Complementary / metabolism
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Dipeptides / chemical synthesis*
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Dipeptides / pharmacokinetics
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Dipeptides / pharmacology*
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Dogs
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Drug Design
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Female
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Growth Hormone / metabolism*
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Half-Life
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Humans
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Indicators and Reagents
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Indoles / pharmacology
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Magnetic Resonance Spectroscopy
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology*
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Pituitary Gland / cytology
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Pituitary Gland / drug effects
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Pituitary Gland / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Solubility
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Spiro Compounds / pharmacology
Substances
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CP 424391
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DNA, Complementary
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Dipeptides
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Indicators and Reagents
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Indoles
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Piperidines
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Pyrazoles
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Spiro Compounds
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Growth Hormone
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ibutamoren mesylate