Preclinical pharmacology of CP-424,391, and orally active pyrazolinone-piperidine growth hormone secretagogue

  title={Preclinical pharmacology of CP-424,391, and orally active pyrazolinone-piperidine growth hormone secretagogue},
  author={Lydia C. Pan and Philip Albert Groton Carpino and Bruce A. Lefker and John A. Ragan and Steven M. Toler and John C. Pettersen and David O. Nettleton and Oicheng Ng and Christine M. Pirie and Kristin L Chidsey-Frink and Bihong Lu and David F. Nickerson and David A. Tess and Michelle A Mullins and David B. Maclean and Paul A DaSilva-Jardine and David Duane Thompson},
Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50=3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine… 
Development of growth hormone secretagogues.
The GH secretagogues act through all four mechanisms to reproduce a young adult physiological GH profile in elderly subjects that was accompanied by increased bone mineral density and lean mass, modest improvements in strength, and improved recovery from hip fracture.
Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro
Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves.
Ghrelin receptor modulators and their therapeutic potential.
Its importance in the field of medicinal chemistry research is set to increase significantly, after the discovery of several compounds able to modulate the ghrelin receptor and inverse agonists have been discovered that are able to reduce weight gain.
Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues
The ghrelin receptor shows a significant constitutive activity which means that in addition to agonists and antagonists, inverse agonists play an important role in receptor modulation, and a strong focus on the regulation of food intake is focused on.
Determination of therapeutics with growth-hormone secretagogue activity in human urine for doping control purposes.
The mass spectrometric dissociation behavior of three acetylcholine esterase inhibitors and a structural analogue to the growth-hormone secretagogue SM-130686 provided substantial information for screening procedures, complementing common methods of sports drug testing.
Growth hormone secretagogues: history, mechanism of action, and clinical development
This review will focus on the research history and the pharmacology of each GHS, which reached randomized clinical trials, and highlight the publicly disclosed clinical trials regarding GHSs.
Novel and Conventional Receptors for Ghrelin, Desacyl-Ghrelin, and Pharmacologically Related Compounds
Benefits mediated through GRLRs or UAG receptors include adipocyte lipid accumulation, myoblast differentiation, osteoblast proliferation, insulin release, cardioprotection, coronary artery constriction, vascular endothelial cell proliferation, and tumor cell proliferation.
Recent Developments in Ghrelin Receptor Ligands
This review summarizes the various types of GHS‐R1a ligands that have been described in the literature and discusses the recent progress made in this research area.
Cognitive enhancing effects of ghrelin receptor agonists
These results demonstrate that the small-molecule ghrelin receptor agonists profiled here readily cross the blood/brain barrier and elicit pro-cognitive effects in recognition and spatial learning and memory tests.
The metabolic fate and disposition of radiolabeled CP-424391 in rats was investigated: fecal and urinary metabolic profiles were consistent in both genders, and radioactivity was widely distributed in all tissues except for the central nervous system.


Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.
A potent, orally active growth hormone (GH) secretagogue L-163,191 belonging to a recently synthesized structural class has been characterized and has been selected for clinical studies.
On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone.
[His1,Lys6] GHRP may be a valuable peptide for investigating the function of the pituitary somatotrophs and has the potential for increasing BW gain of a variety of normal animals by inducing GH release via a direct pituitsary site of action.
Growth Hormone Secretagogues in Clinical Practice
Part 1 Scope of non-GHRH growth hormone secretagogues: synergistic release of growth hormone by GHRP and GHRH - scope and implication structural requirements of growth hormonesecretagogues and clinical applications of pituitary function using growth hormonesecretagogues.
A nonpeptidyl growth hormone secretagogue.
The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Tr phe-Phe-Lys-NH2 (GHRP-6).
Growth hormone secretagogues: characterization, efficacy, and minimal bioactive conformation.
  • R. Mcdowell, K. Elias, T. Somers
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1995
In vitro and in vivo characterization confirms these GH secretagogues as the most potent and smallest (M(r) < 500) reported and illustrates the utility of an interdisciplinary approach to elucidating potential bound-state conformations of flexible peptide ligands.
A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release
A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs.
Oral Administration of the Growth Hormone Secretagogue MK‐677 Increases Markers of Bone Turnover in Healthy and Functionally Impaired Elderly Adults
  • M. Murphy, M. Bach, B. Gertz
  • Medicine
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 1999
Once daily dosing with MK‐677, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and formation.
Treatment with the Oral Growth Hormone Secretagogue MK‐677 Increases Markers of Bone Formation and Bone Resorption in Obese Young Males
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  • Medicine, Biology
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 1998
In conclusion, short‐term treatment of healthy obese male volunteers with the GH secretagogue MK‐677 increases markers of both bone resorption and formation, and large increases in serum levels of IGF‐I and IGF BP‐5 and a transient increase in serum IGFBP‐4 were found.