A Novel 3-Substituted Benzazepinone Growth Hormone Secretagogue (L-692,429)

Schoen, William R.; Pisano, Judith M.; Prendergast, Kristine; Wyvratt, Matthew J.; Fisher, Michael H.; Cheng, Kang; Chan, Wanda; Butler, Bridget; Smith, Roy G.; Ball, Richard G.

doi:10.1021/jm00033a006

Cited by 101 publications

(31 citation statements)

References 11 publications

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“…Using those parameters, the screening of Merck chemical sample collection spotted a racemic benzolactam 2 as a potential lead for GH release stimulation (EC 50 = 3 µM). Further pharmacomodulation of 2 converged in the synthesis of L‐692,429 3 , highly active in vitro (EC 50 = 30 nM) and in vivo 131–133. It succeeded preclinical safety and toxicology studies and was active in human134, 135.…”

Section: Ghrelin Analogues and Their Biological Activitymentioning

confidence: 95%

Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues

Chollet

Meyer

Beck‐Sickinger

2009

Journal of Peptide Science

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Ghrelin is a unique bioactive peptide with respect to both the structure and its biological function. This 28-amino acid peptide is modified with an n-octanoyl group at serine-3, and accordingly is the only lipidated biologically active peptide hormone known so far. Ghrelin binds to the so-called ghrelin or GHS receptor, a member of the class A of G-protein coupled receptors, which leads to Ca(2+) release intracellularly due to the activation of the Gq-system. Interestingly, 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. In this review, the major activities of ghrelin are summarized with a strong focus on the regulation of food intake. So far reported agonists, antagonists and inverse agonists are shown and structure activitiy relationships are discussed. Furthermore, the application of ghrelin ligands as novel anti-obesity drugs is outlined and the state of the art in this field is summarized.

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Section: Ghrelin Analogues and Their Biological Activitymentioning

confidence: 95%

Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues

Chollet

Meyer

Beck‐Sickinger

2009

Journal of Peptide Science

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“…4,5 Significant progress has been made toward identifying small molecules that mimic the mechanism of action and in vivo properties of GHRP-6. Examples are the benzolactam L-692,429 6,7 (2, Figure 1) and the spiropiperidine-based MK-0677 8 (3, Figure 1). Experiments in rat primary pituitary cells indicated that L-692,429 and MK-0677 are mechanistically indistinguishable from the hexapeptide GHRP-6 and, hence, are peptidomimetic agonists.…”

Section: Introductionmentioning

confidence: 99%

Rational Design, Discovery, and Synthesis of a Novel Series of Potent Growth Hormone Secretagogues

et al. 2001

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In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The 3D pharmacophore identified was then used to search 3D databases to explore chemical structures that could be novel GHSs. A number of these were chosen for synthesis and assessment of their ability to release growth hormone (GH) from rat pituitary cells. Among the compounds tested, those with a benzothiazepin scaffold were discovered with micromolar activity. To facilitate lead optimization, a second program, a site-dependent fragment QSAR procedure was developed. This program calculates a library of chemical and physical properties of "fragments" or chemical components in a known pharmacophore and determines which, if any, of these properties are important for the observed activity. The combined use of the 3D pharmacophore and the results of the site-dependent fragment QSAR analysis led to the discovery and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.

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“…First, screenings of small-molecule chemical libraries resulted in nonpeptide in vitro active GH secretagogues. The benzolactam compound L-158,077 [155] directed design towards biphenyltetrazoles such as MK-0751 (L-692,429). MK-0751 releases GH in vitro [155] and in vivo in animals [156] and in humans [157][158][159].…”

mentioning

confidence: 99%

“…The benzolactam compound L-158,077 [155] directed design towards biphenyltetrazoles such as MK-0751 (L-692,429). MK-0751 releases GH in vitro [155] and in vivo in animals [156] and in humans [157][158][159]. Another initial hit from a chemical library, L-368,112, led the design toward the agonist with partial peptide properties ibutamoren (L-163,191, mesylate salt form MK-0677) [160], which has been extensively studied in animals and humans.…”

mentioning

confidence: 99%

Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists

Vodnik¹,

Štrukelj

Lunder³

2015

Horm Metab Res

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In the recent decades, great progress has been made in the development of ghrelin receptor ligands. The discovery of the first in vitro only active peptide growth hormone secretagogue derived from Met-enkephalin was the foundation for later discoveries of the receptor and the endogenous ligand ghrelin. Since then, the scope of peptides, peptidomimetics, and small-molecules targeting the ghrelin receptor, GHS-R1a, has expanded dramatically. Numerous agonists have been tested in animals and several in humans, and a handful have progressed to clinical trials for indications such as growth hormone release, gastric emptying, and cachexia. However, with the exception of the approval of GHRP-2 for diagnostic purposes in Japan, none of the candidates have been successfully introduced into the market. More recently, the attention of researchers has been concentrated on developing antagonists and inverse agonists for pharmacological treatment of the ever-expanding obese and overweight population. In this review, we describe the development of GHS-R1a targeting agonists, antagonists, and inverse agonists. We focus on current and completed clinical trials and the therapeutic potential of currently available ligands.

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A Novel 3-Substituted Benzazepinone Growth Hormone Secretagogue (L-692,429)

Cited by 101 publications

References 11 publications

Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues

Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues

Rational Design, Discovery, and Synthesis of a Novel Series of Potent Growth Hormone Secretagogues

Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists

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