title: Discovery and biological characterization of capromorelin analogues with extended half-lives.
abstract: 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 >or=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 (ED(50)s>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.
authors.affiliation: Pfizer Global Research & Development, Groton Labs, MS8220-3004, Groton, CT 06340, 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: Marianne C
authors.initials: MC
authors.lastname: Murray
authors.forename: Ewell R
authors.initials: ER
authors.lastname: Cook
authors.forename: Joseph N
authors.initials: JN
authors.lastname: DiBrino
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: Sharon K
authors.initials: SK
authors.lastname: Lewis
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: John C
authors.initials: JC
authors.lastname: Pettersen
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: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D013006:Growth Hormone / Q000187:drug effects; D006133:Growth Substances / Q000378:metabolism; D006207:Half-Life; D057927:Hydrophobic and Hydrophilic Interactions; D007334:Insulin-Like Growth Factor I / Q000187:drug effects; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: C433143:CP 424391; D006133:Growth Substances; D010880:Piperidines; D011720:Pyrazoles; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone