RESUMO
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.
Assuntos
Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Hormônio do Crescimento/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Animais , Células Cultivadas , Fenômenos Químicos , Físico-Química , DNA Complementar/metabolismo , Dipeptídeos/farmacocinética , Cães , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Indicadores e Reagentes , Indóis/farmacologia , Espectroscopia de Ressonância Magnética , Piperidinas/farmacocinética , Hipófise/citologia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Pirazóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Solubilidade , Compostos de Espiro/farmacologiaRESUMO
New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values >or=2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.
