Preclinical pharmacology of CP-424,391, an orally active pyrazolidinone-piperidine growth hormone secretagogue

Growth hormone secretagogues (GHSs) represent attractive therapeutic altern atives to recombinant growth hormone (GH), given their ability to amplify p ulsatile hormone secretion in a relatively physiologic manner. CP-424,391 ( 391) is a novel, orally active pyrazolidinone-piperidine GHS. In rat pituit ary cell cultures, 391 stimulated GH release with an EC50 = 3 nM, The addit ion of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP), 3 91 also modulated the effects of GH-releasing hormone and somatostatin on p ituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependen t on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of GH in a dose-dependent manner. Plasma insulin-like growth factor-1 (IGF -1) was elevated progressively over a 5-d course of daily oral dosing in do gs. Chronic oral administration of 391 augmented body weight gain in rats a nd dogs. Thus, the peptidomimetic GHS 391 has potential utility for the tre atment of clinical conditions that could benefit from systemic augmentation of GH and IGF-1 levels.