Ghrelin Receptor Modulators and Their Therapeutic Potential

Costantino, Luca; Barlocco, Daniela

doi:10.4155/fmc.09.9

Cited by 12 publications

(9 citation statements)

References 127 publications

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“…On these bases, several research groups discovered various chemotypes able to modulate GHS-R1a [335]. Worth of note are EP-51389 (( B ), Scheme 1 ) and its derivative JMV-1843 (EP-1572, AESZ-130) (( 5 ), Scheme 1 ), that originated the widest series of GHS-R1a ligands.…”

Section: Neuroprotectionmentioning

confidence: 99%

“…(Scheme 1 ) reports the structures and the design process of the ghrelin modulators reported in the present article. In fact, starting from JMV-1843, a series of substituted 1,2,4-triazoles, acting as agonists, partial agonists, or antagonists, were synthesized and pharmacologically evaluated, but no clear correlations between in vitro and in vivo results have been obtained [335]. …”

Section: Neuroprotectionmentioning

confidence: 99%

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Pathophysiogenesis of Mesial Temporal Lobe Epilepsy: Is Prevention of Damage Antiepileptogenic?

Curia

Lucchi²,

Vinet³

et al. 2014

CMC

182

135

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Temporal lobe epilepsy (TLE) is frequently associated with hippocampal sclerosis, possibly caused by a primary brain injury that occurred a long time before the appearance of neurological symptoms. This type of epilepsy is characterized by refractoriness to drug treatment, so to require surgical resection of mesial temporal regions involved in seizure onset. Even this last therapeutic approach may fail in giving relief to patients. Although prevention of hippocampal damage and epileptogenesis after a primary event could be a key innovative approach to TLE, the lack of clear data on the pathophysiological mechanisms leading to TLE does not allow any rational therapy. Here we address the current knowledge on mechanisms supposed to be involved in epileptogenesis, as well as on the possible innovative treatments that may lead to a preventive approach. Besides loss of principal neurons and of specific interneurons, network rearrangement caused by axonal sprouting and neurogenesis are well known phenomena that are integrated by changes in receptor and channel functioning and modifications in other cellular components. In particular, a growing body of evidence from the study of animal models suggests that disruption of vascular and astrocytic components of the blood-brain barrier takes place in injured brain regions such as the hippocampus and piriform cortex. These events may be counteracted by drugs able to prevent damage to the vascular component, as in the case of the growth hormone secretagogue ghrelin and its analogues. A thoroughly investigation on these new pharmacological tools may lead to design effective preventive therapies.

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Section: Neuroprotectionmentioning

confidence: 99%

Section: Neuroprotectionmentioning

confidence: 99%

Pathophysiogenesis of Mesial Temporal Lobe Epilepsy: Is Prevention of Damage Antiepileptogenic?

Curia

Lucchi²,

Vinet³

et al. 2014

CMC

182

135

View full text Add to dashboard Cite

show abstract

“…A number of small molecule ghrelin receptor antagonists have been described in the literature (see Figure ). − The vast majority of these efforts have focused on centrally acting agents targeted toward the treatment of obesity. We previously reported on a spiro-azetidino-piperidine series that was identified from high-throughput screening (HTS) of our corporate file .…”

mentioning

confidence: 99%

Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate

Bhattacharya

Andrews

Beveridge

et al. 2014

ACS Med. Chem. Lett.

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The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing offtarget pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

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“…This prompted the research of ghrelin receptor antagonist/inverse agonists as antiobesity agents. After the discovery of the ghrelin peptidic antagonist [d-Lys3]GHRP-6, able to reduce food intake and BW gain in lean, ob/ob (leptin-deficient) and DIO mice, several classes of nonpeptidic ghrelin receptor antagonists [75,76] showed promising in vivo activities as antiobesity agents (preclinical researches) [75]. However, results obtained in the presence of some ghrelin antagonists/inverse agonists showed that the effect on BW and feeding not always correlates with the in vitro actions on ghrelin receptor.…”

Section: Ghrelin Antagonists/inverse Agonistsmentioning

confidence: 99%

New Perspectives on the Development of Antiobesity Drugs

Costantino

Barlocco

2015

Future Med. Chem.

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After many years of research, obesity is still a disease with an unmet medical need. Very few compounds have been approved, acting mainly on neuromediators; researches, in recent years, pointed toward compounds potentially safer than first-generation antiobesity drugs, able to interact with one or more (multitarget therapy) receptors for substances produced by the gut, adipose tissue and other targets outside CNS. Other holistic approaches, such as those involving gut microbiota and plant extracts, appeared recently in the literature, and undoubtedly will contribute to the discovery of a valuable therapy for this disease. This review deals with the positive results and the pitfalls obtained following these approaches, with a view on their clinical trial studies.

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Ghrelin Receptor Modulators and Their Therapeutic Potential

Abstract: Taking into account the great number of pathological conditions related to ghrelin, and the discovery of several compounds able to modulate the ghrelin receptor, its importance in the field of medicinal chemistry research is set to increase significantly.

Cited by 12 publications

References 127 publications

Pathophysiogenesis of Mesial Temporal Lobe Epilepsy: Is Prevention of Damage Antiepileptogenic?

Pathophysiogenesis of Mesial Temporal Lobe Epilepsy: Is Prevention of Damage Antiepileptogenic?

Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate

New Perspectives on the Development of Antiobesity Drugs

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