Discovery and biological characterization of capromorelin analogues with extended half-lives |
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Authors: | 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 |
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Affiliation: | Pfizer Global Research & Development, Groton Labs, MS8220-3004, Groton, CT 06340, USA. philip_a_carpino@groton.pfizer.com |
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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 >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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