title: Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine [correction of pyrazolidinone-piperidine] growth hormone secretagogue.
abstract: Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine [corrected] GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50 = 3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of G H in a dose-dependent manner. Plasma insulin-like growth factor-I (IGF-I) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-I levels.
authors.affiliation: Global Research and Development, Pfizer, Inc., Groton, CT 06340, USA [corrected]. lydia_c_pan@groton.pfizer.com
authors.forename: L C
authors.initials: LC
authors.lastname: Pan
authors.forename: P A
authors.initials: PA
authors.lastname: Carpino
authors.forename: B A
authors.initials: BA
authors.lastname: Lefker
authors.forename: J A
authors.initials: JA
authors.lastname: Ragan
authors.forename: S M
authors.initials: SM
authors.lastname: Toler
authors.forename: J C
authors.initials: JC
authors.lastname: Pettersen
authors.forename: D O
authors.initials: DO
authors.lastname: Nettleton
authors.forename: O
authors.initials: O
authors.lastname: Ng
authors.forename: C M
authors.initials: CM
authors.lastname: Pirie
authors.forename: K
authors.initials: K
authors.lastname: Chidsey-Frink
authors.forename: B
authors.initials: B
authors.lastname: Lu
authors.forename: D F
authors.initials: DF
authors.lastname: Nickerson
authors.forename: D A
authors.initials: DA
authors.lastname: Tess
authors.forename: M A
authors.initials: MA
authors.lastname: Mullins
authors.forename: D B
authors.initials: DB
authors.lastname: MacLean
authors.forename: P A
authors.initials: PA
authors.lastname: DaSilva-Jardine
authors.forename: D D
authors.initials: DD
authors.lastname: Thompson
mesh_terms: D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D023421:Models, Animal; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013004:Somatostatin / Q000494:pharmacology; D013997:Time Factors
chemical_list: C433143:CP 424391; D009842:Oligopeptides; D010455:Peptides; D010880:Piperidines; D011720:Pyrazoles; C041048:growth hormone releasing hexapeptide; D013004:Somatostatin; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D002118:Calcium; D006854:Hydrocortisone