2. Academic Validation
  3. Discovery and biological characterization of capromorelin analogues with extended half-lives

Discovery and biological characterization of capromorelin analogues with extended half-lives

  • Bioorg Med Chem Lett. 2002 Nov 18;12(22):3279-82. doi: 10.1016/s0960-894x(02)00734-5.
Philip A Carpino 1,  Bruce A Lefker,  Steven M Toler,  Lydia C Pan,  John R Hadcock,  Marianne C Murray,  Ewell R Cook,  Joseph N DiBrino,  Shari L DeNinno,  Kristin L Chidsey-Frink,  William A Hada,  John Inthavongsay,  Sharon K Lewis,  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,  John C Pettersen,  Paul A DaSilva-Jardine,  Theresa C Wilson,  David D Thompson
Affiliations

Affiliation

  • 1 Pfizer Global Research & Development, Groton Labs, MS8220-3004, Groton, CT 06340, USA. [email protected]
PMID: 12392732 DOI: 10.1016/s0960-894x(02)00734-5
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.

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