Discovery and biological characterization of capromorelin analogues with extended half-lives.
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.
Carpino
Philip A
PA
Pfizer Global Research & Development, Groton Labs, MS8220-3004, Groton, CT 06340, USA. philip_a_carpino@groton.pfizer.com
Lefker
Bruce A
BA
Toler
Steven M
SM
Pan
Lydia C
LC
Hadcock
John R
JR
Murray
Marianne C
MC
Cook
Ewell R
ER
DiBrino
Joseph N
JN
DeNinno
Shari L
SL
Chidsey-Frink
Kristin L
KL
Hada
William A
WA
Inthavongsay
John
J
Lewis
Sharon K
SK
Mangano
F Michael
FM
Mullins
Michelle A
MA
Nickerson
David F
DF
Ng
Oicheng
O
Pirie
Christine M
CM
Ragan
John A
JA
Rose
Colin R
CR
Tess
David A
DA
Wright
Ann S
AS
Yu
Li
L
Zawistoski
Michael P
MP
Pettersen
John C
JC
DaSilva-Jardine
Paul A
PA
Wilson
Theresa C
TC
Thompson
David D
DD
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
C433143:CP 424391; D006133:Growth Substances; D010880:Piperidines; D011720:Pyrazoles; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone