Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin
| Autor: | Philip A, Carpino, Bruce A, Lefker, Steven M, Toler, Lydia C, Pan, John R, Hadcock, Ewell R, Cook, Joseph N, DiBrino, Anthony M, Campeta, Shari L, DeNinno, Kristin L, Chidsey-Frink, William A, Hada, John, Inthavongsay, F Michael, Mangano, Michelle A, Mullins, David F, Nickerson, Oicheng, Ng, Christine M, Pirie, John A, Ragan, Colin R, Rose, David A, Tess, Ann S, Wright, Li, Yu, Michael P, Zawistoski, Paul A, DaSilva-Jardine, Theresa C, Wilson, David D, Thompson |
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| Rok vydání: | 2003 |
| Předmět: |
DNA
Complementary Indoles Magnetic Resonance Spectroscopy Chemical Phenomena Chemistry Physical Dipeptides Rats Rats Sprague-Dawley Dogs Piperidines Solubility Drug Design Growth Hormone Pituitary Gland Animals Humans Pyrazoles Female Indicators and Reagents Spiro Compounds Rats Wistar Cells Cultured Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry. 11(4) |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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