Growth hormone secretagogues

MK-677, an orally active spiroindoline-based growth hormone secretagogue (GHS) agonist, discovered by Merck and currently in Phase II clinical studies, was synthesized with a Fischer indolization as a key step. The synthesis of this agonist involved a Fischer indole/reduction process and was achieved in 48% overall yield from the relatively cheap starting material, isonipecotic acid 72. ... 

Carpino et al. recently disclosed the synthesis of the fused pyrazolinone-piperidine dipeptide 56 with potent growth hormone secretagogue activity. The synthesis of the intermediate pyrazolone was accomplished by reacting the ketoester 54 with methyl hydrazine in refluxing ethanol. ... 

Copinschi, G., Leproult, R., Van, O. A. et al. (1997). Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology 66, 278-86. 

Guan, X. M., Yu, H., Palyha, O. C. et al. (1997). Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res. Mol. Brain Res. 48, 23-9. 

Mitchell, V., Bouret, S., Beauvillain, J. C. et al. (2001). Comparative distribution of mRNA encoding the growth hormone secretagogue-receptor (GHS-R) in Microcebus murinus (Primate, lemurian) and rat forebrain and pituitary. J. Comp. Neurol. 429, 469-89. 

A series of growth hormone secretagogues were prepared via peptide coupling to acid 299. These molecules were rationally designed by computational methods <2001JME4082>. 

Carreira, M. C., Camina, J. P., Smith, R. G. and Casanueva, F. F., 2004, Agonist-specific coupling of growth hormone secretagogue receptor type la to different intracellular signaling systems. Role of adenosine, Neuroendocrinology, 79, pp 13-25. 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

Cheng K, Chan WWS, Butler B, Wie L, Smith RG (1993) A novel non-peptidyl growth hormone secretagogue. Horm Res 40 109-115... 

Figure 15.55. GHRP-6 and ghrelin non-peptide derivatives as growth hormone secretagogues inhibitors.

S. Frascarelli, S. Ghelardoni, S. Ronca-Testoni and R. Zucchi, Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart, Basic Res. Cardiol. 98,401-405 (2003). 

Compound 19 is a potent benzazepinone growth hormone secretagogue that suffers from poor bioavailability in dog (F = 2%) The molecule exists in a zwitterionic form that is presumably the cause for the poor bioavailability. Two key structural modifications were required to improve the PK profile. The acidic tetrazole was replaced with a number of amide and urea substituents before identifying the key methyl urea moiety, which resulted in an 8-fold increase in activity over 19. Further, shortening the amino acid side chain decreased the pK of the amine from 9.2 to 7.5. The combination of changes provided compound 20, which resulted in a 60-fold increase in activity over parent compound 19 and increased oral bioavailability in dogs to 24%. 

Zhao, H., Xin, Z., Liu, G. et al. Discovery of tetralin carboxamide growth hormone secretagogue receptor antagonists via scaffold manipulation. J. Med. Chem. 2004, 47, 6655-6651. 

Constanzer, M. Chavez-Eng, C. Matuszewski, B. Determination of a Thermally Labile Metabolite of a Novel Growth Hormone Secretagogue in Human and Dog Plasma by Liquid Chromatography with Ion Spray Tandem Mass Spectrometric Detection, J. Chromatogr. B 760,45-53 (2001). 

Chromone derivatives, in particular 2-spiro-chroman-4(lF/)-ones, are ubiquitous in nature and possess various biological activities which include antiarrhythmic, anti-HIV, antidiabetic, acetyl-CoA carboxylase (ACC) inhibitor, vanilloid receptor antagonist, growth hormone secretagogues, histamine receptor antagonist, and... 

A potent, orally bioavailable benzazepinone growth hormone secretagogue. J. Med. Chem. 41 1716-1728. 

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