1. Academic Validation
  2. Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin

Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin

  • Bioorg Med Chem. 2003 Feb 20;11(4):581-90. doi: 10.1016/s0968-0896(02)00433-9.
Philip A Carpino 1 Bruce A Lefker Steven M Toler Lydia C Pan John R Hadcock Ewell R Cook Joseph N DiBrino Anthony M Campeta Shari L DeNinno Kristin L Chidsey-Frink William A Hada John Inthavongsay F Michael Mangano Michelle A Mullins David F Nickerson Oicheng Ng Christine M Pirie John A Ragan Colin R Rose David A Tess Ann S Wright Li Yu Michael P Zawistoski Paul A DaSilva-Jardine Theresa C Wilson David D Thompson
Affiliations

Affiliation

  • 1 Pfizer Global Research and Development, Groton Labs, MS8220-3004, Eastern Point Rd, CT 06340, Groton, USA. philip_a_carpino@groton.pfizer.com
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.

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