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Carpino, P.A. et al.

Carpino, Lefker, Toler, Pan, Hadcock, Murray, Cook, DiBrino, DeNinno, Chidsey-Frink, Hada, Inthavongsay, Lewis, Mangano, Mullins, Nickerson, Ng, Pirie, Ragan, Rose, Tess, Wright, Yu, Zawistoski, Pettersen, DaSilva-Jardine, Wilson, Thompson,

Discovery and biological characterization of capromorelin analogues with extended half-lives.

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.[1]

References

Discovery and biological characterization of capromorelin analogues with extended half-lives. Carpino, P.A., Lefker, B.A., Toler, S.M., Pan, L.C., Hadcock, J.R., Murray, M.C., Cook, E.R., DiBrino, J.N., DeNinno, S.L., Chidsey-Frink, K.L., Hada, W.A., Inthavongsay, J., Lewis, S.K., Mangano, F.M., Mullins, M.A., Nickerson, D.F., Ng, O., Pirie, C.M., Ragan, J.A., Rose, C.R., Tess, D.A., Wright, A.S., Yu, L., Zawistoski, M.P., Pettersen, J.C., DaSilva-Jardine, P.A., Wilson, T.C., Thompson, D.D. Bioorg. Med. Chem. Lett. (2002) [Pubmed]

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