Author/Authors :
Philip A. Carpino، نويسنده , , Bruce A. Lefker، نويسنده , , Steven M. Toler، نويسنده , , Lydia C. Pan، نويسنده , , John R. Hadcock، نويسنده , , Ewell R. Cook، نويسنده , , Joseph N. Dibrino، نويسنده , , Anthony M Campeta، نويسنده , , Shari L. DeNinno، نويسنده , , Kristin L. Chidsey-Frink، نويسنده , , William A. Hada، نويسنده , , John Inthavongsay، نويسنده , , F. Michael Mangano، نويسنده , , Michelle A. Mullins، نويسنده , , David F Nickerson، نويسنده , , Oicheng Ng، نويسنده , , Christine M. Pirie، نويسنده , , John A. Ragan، نويسنده , , Colin R Rose، نويسنده , , David A. Tess، نويسنده , , et al.، نويسنده ,
Abstract :
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a Ki=7 nM, rat pituicyte EC50=3 nM) and the des-methyl analogue 5c (hGHS-R1a Ki=17 nM, rat pituicyte EC50=3 nM), increased plasma GH levels in an anesthesized rat model, with ED50 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.
