Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin.
Bioorg Med Chem
; 11(4): 581-90, 2003 Feb 20.
Article
em En
| MEDLINE
| ID: mdl-12538023
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.
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Pirazóis
/
Hormônio do Crescimento
/
Dipeptídeos
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article