| Literature DB >> 12538023 |
Philip A Carpino1, Bruce A Lefker, Steven M Toler, Lydia C Pan, John R Hadcock, Ewell R Cook, Joseph N DiBrino, Anthony M Campeta, Shari L DeNinno, Kristin L Chidsey-Frink, William A Hada, John Inthavongsay, F Michael Mangano, Michelle A Mullins, David F Nickerson, Oicheng Ng, Christine M Pirie, John A Ragan, Colin R Rose, David A Tess, Ann S Wright, Li Yu, Michael P Zawistoski, Paul A DaSilva-Jardine, Theresa C Wilson, David D Thompson.
Abstract
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.Entities:
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Year: 2003 PMID： 12538023 DOI： 10.1016/s0968-0896(02)00433-9
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641