Discovery and biological characterization of capromorelin analogues with extended half-lives.
作者信息
Carpino Philip A, Lefker Bruce A, Toler Steven M, Pan Lydia C, Hadcock John R, Murray Marianne C, Cook Ewell R, DiBrino Joseph N, DeNinno Shari L, Chidsey-Frink Kristin L, Hada William A, Inthavongsay John, Lewis Sharon K, Mangano F Michael, Mullins Michelle A, Nickerson David F, Ng Oicheng, Pirie Christine M, Ragan John A, Rose Colin R, Tess David A, Wright Ann S, Yu Li, Zawistoski Michael P, Pettersen John C, DaSilva-Jardine Paul A, Wilson Theresa C, Thompson David D
机构信息
Pfizer Global Research & Development, Groton Labs, MS8220-3004, Groton, CT 06340, USA.
出版信息
Bioorg Med Chem Lett. 2002 Nov 18;12(22):3279-82. doi: 10.1016/s0960-894x(02)00734-5.
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.
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