Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor

McClure, Kim F.; Jackson, Margaret; Cameron, Kimberly O.; Kung, Daniel W.; Perry, David A.; Orr, Suvi T. M.; Zhang, Yingxin; Kohrt, Jeffrey T.; Tu, Meihua; Gao, Hua; Fernando, Dilinie P.; Jones, Ryan M.; Erasga, Noe; Wang, Guoqiang; Polívková, Jana; Jiao, Wenhua; Swartz, Roger; Ueno, Hirokazu; Bhattacharya, Samit; Stock, Ingrid A.; Varma, Sam; Bagdasarian, Victoria; Pérez, Sylvie; Kelly-Sullivan, Dawn; Wang, Ruduan; Kong, Jimmy; Cornelius, Peter; Michael, Laura; Lee, Eun-Sun; Janssen, Ann M.; Steyn, Stefanus J.; Lapham, Kimberly; Goosen, Theunis C.

doi:10.1016/j.bmcl.2013.07.044

Cited by 27 publications

(26 citation statements)

References 20 publications

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“…Thus, a series of compounds of general formula (3) was prepared, with some of these compounds (the most interesting was compound 4) acting in the CNS. However, it was reported [81] that the company abandoned this development program owing to the inability to develop a CNS target biomarker and to further improve the functional potency of the compound. At the same time, emerging ghrelin biology studies suggested that blocking ghrelin signaling had the potential to ameliorate diabetes through direct action on the pancreas [82].…”

Section: New Chemical Entities: Ghrelin Antagonists and Inverse Agonistsmentioning

confidence: 97%

“…Pfizer [42,80,81] reported the development of spyrocyclic piperidine-azetidine class of compounds as ghrelin inverse agonists addressed to the CNS, with a view to finding compounds provided with beneficial effects on body weight and glucose homeostasis, or to the periphery, addressed at type 2 diabetes treatment [20,80]. Screening based on radioligand binding assay utilizing [ 125 I]ghrelin and a scintillation proximity assay format was setup to screen for ligand affinity; this assay was followed by a GTP-g-S assay to discriminate the functional profile of the selected compounds.…”

Section: New Chemical Entities: Ghrelin Antagonists and Inverse Agonistsmentioning

confidence: 99%

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Ghrelin receptor modulators: a patent review (2011 – 2014)

Costantino

Barlocco

2014

Expert Opinion on Therapeutic Patents

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Ghrelin appears to mediate a myriad of actions, and some of these appear to be due to unknown mechanisms (a second putative ghrelin receptor, putative receptors for unacylated ghrelin); several agonists, antagonists and inverse agonists at ghrelin receptor have been developed but their mechanism of action into CNS is poorly understood. The therapeutic potential of compounds acting on ghrelin receptor is still to be fully assessed, but the results obtained to date are encouraging for the successful clinical translation of compounds able to treat several pathologies.

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Section: New Chemical Entities: Ghrelin Antagonists and Inverse Agonistsmentioning

confidence: 97%

Section: New Chemical Entities: Ghrelin Antagonists and Inverse Agonistsmentioning

confidence: 99%

Ghrelin receptor modulators: a patent review (2011 – 2014)

Costantino

Barlocco

2014

Expert Opinion on Therapeutic Patents

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“…Performing these studies in mice lacking α 1 -adrenoceptors may assist in confirming these conclusions. A number of off-target effects for other ghrelin receptor ligands at known non-ghrelin receptors have been identified, including β 3 -adrenoceptor agonist activity by (4-[(aminocarbonyl)amino]-N-[4-(2-aminoethyl)phenyl]benzenesulfonamides (Pasternak et al, 2009) and muscarinic receptor agonist activity by spiro-azetidine-piperidine analogues (McClure et al, 2013). In our study, propranolol did not reduce the vasodilatator action of ulimorelin, excluding a role for β 3 -adrenoceptors.…”

Section: Stimulusmentioning

confidence: 99%

Analysis of the ghrelin receptor-independent vascular actions of ulimorelin

Broad

Callaghan

Sanger

et al. 2015

European Journal of Pharmacology

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Ulimorelin (TZP101) is a ghrelin receptor agonist that stimulates intestinal motility, but also reduces blood pressure in rodents and humans and dilates blood vessels. It has been proposed as a treatment for intestinal motility disorders. Here we investigated the mechanisms through which ulimorelin affects vascular diameter. Actions of ulimorelin on wall tension of rodent arteries were investigated and compared with other ghrelin receptor agonists. Saphenous, mesenteric and basilar arteries were obtained from Sprague-Dawley rats (male, 8 weeks) and saphenous arteries were obtained from wild type or ghrelin receptor null mice. These were mounted in myography chambers to record artery wall tension. Ulimorelin (0.03-30µM) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6µM; Imax=66±5%; n=3-6) and mesenteric arteries (IC50=5µM, Imax=113±16%; n=3-4), but not those contracted by U46619, ET-1 or 60mM [K(+)]. Relaxation of phenylephrine-constricted arteries was not observed with ghrelin receptor agonists TZP102, capromorelin or AZP-531. In rat saphenous and basilar arteries, ulimorelin (10-100µM) and TZP102 (10-100µM) constricted arteries (EC50=9.9µM; Emax=50±7% and EC50=8µM; Emax=99±16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3µM or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1-10µM, caused a surmountable rightward shift in the response to phenylephrine (0.01-1000µM; pA2=5.7; n=3-4). Ulimorelin had similar actions in mouse saphenous artery from both wild type and ghrelin receptor null mice. We conclude that ulimorelin causes vasorelaxation through competitive antagonist action at α1-adrenoceptors and a constrictor action not mediated via the ghrelin receptor.

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“…However, compound 2 suffered from several off-target activities in a Cerep safety panel, and the physicochemical properties were not ideal for further development. 20 The project team noted that the requisite effect should be derived from action on the islet cells in pancreas; as such, peripheral restriction will have advantages in safety and side effect profile. 20 Variations of 2 at both the C(5) position of the indane ring and the piperidine acetamide portion to access compounds of increased lipophilic efficiency (LipE) 23,24 were investigated and compound 1 (PF-5190457) was discovered as a peripherally acting potent ghrelin inverse agonist.…”

mentioning

confidence: 99%

“…c Geometric mean ± standard error of ≥3 measurements, unless noted otherwise. d human ghrelin receptor agonist/antagonist/inverse agonist GTP-γ-S functional assay as published in ref 20. e Negative % effect indicates an inverse agonist.…”

mentioning

confidence: 99%

Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

Orr

Beveridge

Bhattacharya

et al. 2014

ACS Med. Chem. Lett.

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Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHSR1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series.

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Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor

Cited by 27 publications

References 20 publications

Ghrelin receptor modulators: a patent review (2011 – 2014)

Ghrelin receptor modulators: a patent review (2011 – 2014)

Analysis of the ghrelin receptor-independent vascular actions of ulimorelin

Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

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