Synthesis and pharmacological profile of an orally-active growth hormone secretagogue, SM-130686

Combinatorial Chemistry & High Throughput Screening
Jun NagamineMutsuo Taiji

Abstract

Hypothalamic hormones physiologically regulate pulsatile release of growth hormone (GH) from the anterior pituitary gland. Since the discovery of these hormones in the 1970s, several new chemically synthesized peptidyl and non-peptidyl derivatives have been proved to stimulate and amplify GH secretion, and this series of molecules has been named the growth hormone secretagogues (GHSs). One of these compounds led to the discovery of a GPCR-type receptor for GHSs (GHS-R), and subsequently the endogenous ligand for the receptor has been identified, and is referred to as ghrelin. The identification of GHSs as physiological regulators of GH secretion encouraged us to examine our GHSs pharmacologically. We previously reported that novel oxindole derivatives have been identified as GHS-R agonists from our internal chemical library. Among these derivatives, (+)-6-carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity in vitro with a good pharmacokinetic profile in rats (bioavailability of 28%). In this article, we review the synthesis and pharmacological evaluation of SM-130686. SM-130686 binds specifically to GHS-R and increases the Ca(2+) concentration in Chines...Continue Reading

Citations

Mar 23, 2005·Bioorganic & Medicinal Chemistry Letters·Teruhisa TokunagaRyu Nagata
Jun 26, 2012·Pharmacology & Therapeutics·Christa E MüllerYounis Baqi
Oct 20, 2006·Rapid Communications in Mass Spectrometry : RCM·Mario ThevisWilhelm Schänzer

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