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Preclinical, Journal: Pharmacological GHSR (ghrelin receptor) blockade reduces alcohol binge-like drinking in male and female mice. (Pubmed Central) - Aug 7, 2023 Systemic administration of the GHSR antagonists JMV2959, PF-5190457, PF-6870961, and HM-04 reduced alcohol intake in both male and female mice...These findings suggest that central GHSR mediates binge-like alcohol intake. These data reveal novel pharmacological compounds with translational potential in the treatment of AUD and provide further evidence of the GHSR as a potential treatment target for AUD.
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Trial termination: A Novel Compound for Alcoholism Treatment: A Translational Strategy - Part II (clinicaltrials.gov) - Mar 16, 2022 P2, N=42, Terminated, Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies. Completed --> Terminated; Early termination of the study due to the COVID-19 pandemic
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Review, Journal: Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder. (Pubmed Central) - Mar 4, 2022 Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.
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Journal: Molecular mechanism of agonism and inverse agonism in ghrelin receptor. (Pubmed Central) - Feb 15, 2022 Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin...Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.
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Clinical, Review, Journal, Combination therapy: Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies. (Pubmed Central) - Sep 3, 2021 In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge...On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.
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Trial completion, Trial completion date, Trial primary completion date: A Novel Compound for Alcoholism Treatment: A Translational Strategy - Part II (clinicaltrials.gov) - Sep 11, 2020 P2, N=42, Completed, PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder. Recruiting --> Completed | Trial completion date: Dec 2020 --> Sep 2020 | Trial primary completion date: Dec 2020 --> Feb 2020
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Review, Journal: Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder. (Pubmed Central) - May 7, 2020 PF-5190457, a GHS-R1a blocker, has been shown to be safe and tolerable when co-administered with alcohol...Collectively, the existing literature supports further examination of the ghrelin system as a therapeutic target for AUD. More research is also needed to understand the biobehavioral and molecular mechanisms underlying ghrelin's functions and to examine different interventional approaches to target the ghrelin system for AUD treatment.
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Review, Journal: Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges. (Pubmed Central) - Apr 15, 2020 PF-05190457 is the first inverse agonist of the ghrelin receptor tested in humans shown to inhibit growth hormone secretion, gastric emptying, and reduce postprandial glucose levels...Although various highly promising agents targeting ghrelin signaling exist, so far, they were mostly only tested in vitro or in animal models. Further research in humans is thus needed to further assess the effects of ghrelin antagonism on body weight especially under conditions of obesity.
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Trial completion date, Trial primary completion date: A Novel Compound for Alcoholism Treatment: A Translational Strategy - Part II (clinicaltrials.gov) - Sep 26, 2019 P2, N=55, Recruiting, Further, the application of the method was demonstrated by measuring the concentration of PF-5190457 and its hydroxy metabolite in patient plasma samples from 100 mg dose. Trial completion date: Dec 2019 --> Dec 2020 | Trial primary completion date: Dec 2019 --> Dec 2020
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Trial initiation date, Trial primary completion date: A Novel Compound for Alcoholism Treatment: A Translational Strategy - Part II (clinicaltrials.gov) - Oct 22, 2018 P2, N=55, Recruiting, Future research should investigate the potential mechanism(s) underlying this effect. Initiation date: Mar 2016 --> Jun 2016 | Trial primary completion date: Dec 2018 --> Dec 2019
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Trial completion, Enrollment change, Trial primary completion date: A Novel Compound for Alcoholism Treatment (clinicaltrials.gov) - Oct 5, 2015 P1, N=14, Completed, Initiation date: Mar 2016 --> Jun 2016 | Trial primary completion date: Dec 2018 --> Dec 2019 Recruiting --> Completed | N=20 --> 14 | Trial primary completion date: Jun 2017 --> Oct 2015
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Enrollment change: A Novel Compound for Alcoholism Treatment (clinicaltrials.gov) - Dec 7, 2014 P1, N=20, Recruiting, Recruiting --> Completed | N=20 --> 14 | Trial primary completion date: Jun 2017 --> Oct 2015 N=15 --> 20
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