193274-04-3Relevant articles and documents
Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs): Discovery of capromorelin
Carpino, Philip A.,Lefker, Bruce A.,Toler, Steven M.,Pan, Lydia C.,Hadcock, John R.,Cook, Ewell R.,DiBrino, Joseph N.,Campeta, Anthony M.,DeNinno, Shari L.,Chidsey-Frink, Kristin L.,Hada, William A.,Inthavongsay, John,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.,DaSilva-Jardine, Paul A.,Wilson, Theresa C.,Thompson, David D.
, p. 581 - 590 (2007/10/03)
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 an
Discovery and biological characterization of capromorelin analogues with extended half-lives
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,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.
, p. 3279 - 3282 (2007/10/03)
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.
