title: Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin.
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.
authors.affiliation: Pfizer Global Research and Development, Groton Labs, MS8220-3004, Eastern Point Rd, CT 06340, Groton, USA. philip_a_carpino@groton.pfizer.com
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lefker
authors.forename: Steven M
authors.initials: SM
authors.lastname: Toler
authors.forename: Lydia C
authors.initials: LC
authors.lastname: Pan
authors.forename: John R
authors.initials: JR
authors.lastname: Hadcock
authors.forename: Ewell R
authors.initials: ER
authors.lastname: Cook
authors.forename: Joseph N
authors.initials: JN
authors.lastname: DiBrino
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Campeta
authors.forename: Shari L
authors.initials: SL
authors.lastname: DeNinno
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Chidsey-Frink
authors.forename: William A
authors.initials: WA
authors.lastname: Hada
authors.forename: John
authors.initials: J
authors.lastname: Inthavongsay
authors.forename: F Michael
authors.initials: FM
authors.lastname: Mangano
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Mullins
authors.forename: David F
authors.initials: DF
authors.lastname: Nickerson
authors.forename: Oicheng
authors.initials: O
authors.lastname: Ng
authors.forename: Christine M
authors.initials: CM
authors.lastname: Pirie
authors.forename: John A
authors.initials: JA
authors.lastname: Ragan
authors.forename: Colin R
authors.initials: CR
authors.lastname: Rose
authors.forename: David A
authors.initials: DA
authors.lastname: Tess
authors.forename: Ann S
authors.initials: AS
authors.lastname: Wright
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zawistoski
authors.forename: Paul A
authors.initials: PA
authors.lastname: DaSilva-Jardine
authors.forename: Theresa C
authors.initials: TC
authors.lastname: Wilson
authors.forename: David D
authors.initials: DD
authors.lastname: Thompson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018076:DNA, Complementary / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012995:Solubility; D013141:Spiro Compounds / Q000494:pharmacology
chemical_list: C433143:CP 424391; D018076:DNA, Complementary; D004151:Dipeptides; D007202:Indicators and Reagents; D007211:Indoles; D010880:Piperidines; D011720:Pyrazoles; D013141:Spiro Compounds; D013006:Growth Hormone; C094817:ibutamoren mesylate