193274-00-9Relevant articles and documents
Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists
Azimioara, Mihai,Alper, Phil,Cow, Christopher,Mutnick, Daniel,Nikulin, Victor,Lelais, Gerald,Mecom, John,McNeill, Matthew,Michellys, Pierre-Yves,Wang, Zhiliang,Reding, Esther,Paliotti, Michael,Li, Jing,Bao, Dingjiu,Zoll, Jocelyn,Kim, Young,Zimmerman, Matthew,Groessl, Todd,Tuntland, Tove,Joseph, Sean B.,McNamara, Peter,Seidel, H. Martin,Epple, Robert
, p. 5478 - 5483 (2015/01/09)
Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduc
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.
