2. Academic Validation
  3. 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
PMID: 12538023 DOI: 10.1016/s0968-0896(02)00433-9
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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