Synthesis and Pharmacological Profile of an Orally-Active Growth Hormone Secretagogue, SM-130686

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 Chinese hamster ovary cells expressing recombinant GHS-R. Maximal enhancement of the intracellular Ca(2+) concentration induced by SM-130686 treatment was approximately 55% that induced by ghrelin, suggesting that SM-130686 may be a partial GHS-R agonist. Also, in in vivo studies, oral administration of SM-130686 increased body length and fat-free mass gain. We compare the pharmacological profile of SM-130686 with other GHSs, including GHRH and ghrelin, and discuss the therapeutic usefulness of GHSs against several disorders, as well as for treatment of GH deficiency.

Heterogeneity of Ghrelin/Growth Hormone Secretagogue Receptors

“…Particularly remarkable is the broad range of chemistries of the GHS developed in the last few years by several pharmaceutical groups. They consist of low-molecular-weight peptides, partial peptides and non-peptide molecules [6,13,14,15]. Several GHRP/GHS candidates were studied clinically, but none have reached the market [6, 11, 12].…”

Structural Analogy — Direct Similarity Versus Topographical Complementarity

“…Human hormone effectors such as: meclinertant (neurotensin receptor, Figure 13), ezlopitant (neurokinin receptor) [61], CP-154,526 (corticotropin-releasing hormone receptor) [62], SM-130,686 (growth hormone secretatogue) [63], asperlicin (cholecysatokinin receptor) [64] or galantanamine (nicotinic receptor) [65], have been discovered either by serendipity or were isolated from natural sources. Their structures are significantly different from natural hormones ( Figure 22) and therefore it is very difficult to design drugs basing on binding modes of these hormones with their receptors.…”

A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

“…3 3-Hydroxyoxindoles with a quaternary benzylic centre are a useful class of compounds also found in several drug candidates, including the potent, orally active growth hormone secretagogue SM-130686, 4 a drug that currently is under investigation for the treatment of growth hormone deficiency and other medical conditions (Figure 1). 5 There are a number of reports on the enantioselective formation of quaternary carbon centers at the 3-position of oxindoles. 6 For example, Hartwig first reported the palladiumcatalysed synthesis of oxindoles by amide α-arylation with ees of up to 67%; 7 This was later improved upon by Kündig using modified N-heterocyclic carbenes 8 and Marsden has reported several methods for the synthesis of 3-hydroxy-and 3-aminooxindoles.…”