Author/Authors :
Philip A. Carpino، نويسنده , , Bruce A. Lefker، نويسنده , , Steven M. Toler، نويسنده , , Lydia C. Pan، نويسنده , , John R. Hadcock، نويسنده , , Marianne C. Murray، نويسنده , , Ewell R. Cook، نويسنده , , Joseph N. Dibrino، نويسنده , , Shari L. DeNinno، نويسنده , , Kristin L. Chidsey-Frink، نويسنده , , William A. Hada، نويسنده , , John Inthavongsay، نويسنده , , Sharon K. Lewis، 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 , , et al.، نويسنده ,
Abstract :
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 ≥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 (ED50s>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.
