Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin.
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.
Carpino
Philip A
PA
Pfizer Global Research and Development, Groton Labs, MS8220-3004, Eastern Point Rd, CT 06340, Groton, USA. philip_a_carpino@groton.pfizer.com
Lefker
Bruce A
BA
Toler
Steven M
SM
Pan
Lydia C
LC
Hadcock
John R
JR
Cook
Ewell R
ER
DiBrino
Joseph N
JN
Campeta
Anthony M
AM
DeNinno
Shari L
SL
Chidsey-Frink
Kristin L
KL
Hada
William A
WA
Inthavongsay
John
J
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
DaSilva-Jardine
Paul A
PA
Wilson
Theresa C
TC
Thompson
David D
DD
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
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