GHS-R1a Drug Development Landscape

Targeting Strategies and Challenges

Developing drugs targeting GHS-R1a presents unique challenges due to the receptor's high constitutive activity, complex signaling involving multiple G proteins and β-arrestin, and its tendency to form dimers [1, 2]. However, these complexities also offer opportunities for nuanced therapeutic strategies beyond simple agonism or antagonism. Key approaches include:

• Agonism: Mimicking ghrelin to stimulate appetite and GH release (for cachexia, sarcopenia).
• Antagonism: Blocking ghrelin binding to reduce appetite (for obesity).
• Inverse Agonism: Suppressing the receptor's high constitutive activity, potentially offering greater efficacy than simple antagonism for conditions like obesity [1].
• Biased Agonism/Antagonism: Developing ligands that selectively modulate specific downstream pathways (e.g., G protein vs. β-arrestin) to achieve desired effects while minimizing side effects [1].
• Targeting GOAT: Inhibiting the enzyme that activates ghrelin offers an alternative approach to reduce GHS-R1a signaling, potentially avoiding direct receptor modulation side effects [2].

The focus has largely shifted towards nonpeptide small molecules due to their better pharmacokinetic properties compared to peptide-based ligands [1].

GHS-R1a Agonists

Several small molecule GHS-R1a agonists have been developed, primarily targeting conditions requiring appetite stimulation and anabolic effects:

• Anamorelin (Adlumiz): Developed by Ono Pharmaceutical and Helsinn Healthcare. Approved in Japan for cancer cachexia. It increases appetite, body weight, muscle mass, and GH levels [1].
• Capromorelin: Developed by Pfizer, later licensed for veterinary use (Aratana Therapeutics) and human use (Teijin Pharma). Investigated for cachexia and sarcopenia [1].
• Ibutamoren (MK-0677): Developed by Merck. Showed efficacy in increasing GH/IGF-1 levels and muscle mass, but development was halted due to concerns about potential congestive heart failure risk in elderly patients [1].
• Ulimorelin (TZP-101): Developed by Tranzyme Pharma (later Ocera/Mallinckrodt). Primarily targeted GI motility disorders like postoperative ileus and diabetic gastroparesis, reaching advanced clinical trials [1].
• Other Scaffolds: Companies like AstraZeneca explored various chemical scaffolds including indane diamides, pyrrolidines, piperidines, 2-pyridones, quinolones, and 7-azanorbornanes, though some faced challenges like off-target activity [1].

GHS-R1a Antagonists and Inverse Agonists

Targeting obesity and addiction has driven the development of GHS-R1a antagonists and inverse agonists:

• PF-5190457: Developed by Pfizer, this spiro-azetidine-piperidine compound is a potent inverse agonist. It progressed to Phase 1 and 2 clinical trials for obesity and alcohol use disorder, demonstrating target engagement and effects on appetite/cravings in humans [1]. Its metabolite, PF-6870961, was also studied.
• Macimorelin-Derived Antagonists: The agonist Macimorelin scaffold was modified to create antagonists/inverse agonists like JMV 2959 [1].
• Other Scaffolds: AstraZeneca developed acylurea and 2-aminoalkyl nicotinamide antagonists. Bayer developed YIL781, identified as a biased antagonist. Abbott developed Abb13d, a Gαq/11 inverse agonist [1].

The development of inverse agonists is particularly interesting due to the high constitutive activity of GHS-R1a, offering a potential advantage over neutral antagonists [1].

Clinical Trials Overview

The clinical development of GHS-R1a modulators has seen mixed results. Agonists like Anamorelin have achieved regulatory approval in specific regions for cachexia, validating the target for this indication [1]. Ulimorelin showed promise for GI motility disorders in Phase 2 trials. However, agonists like Ibutamoren faced safety hurdles [1]. Antagonists/inverse agonists like PF-5190457 demonstrated proof-of-concept in early human trials for obesity and addiction but have not yet reached market approval [1]. The complexity of GHS-R1a signaling and potential off-target effects remain significant challenges in clinical development.

Future Directions

Future research and development efforts in the GHS-R1a field include:

• Biased Ligands: Continued focus on developing ligands that selectively target specific signaling pathways to optimize efficacy and minimize side effects [1, 2].
• PET Imaging Agents: Development of radiolabeled GHS-R1a ligands (e.g., 18F-labeled) for use in Positron Emission Tomography (PET) allows for non-invasive visualization of receptor expression and occupancy, aiding diagnosis, patient stratification, and monitoring treatment response in clinical trials [1].
• Targeting GOAT: Further exploration of small molecule GOAT inhibitors as an alternative strategy to modulate the ghrelin system [2].
• Understanding Dimerization: Investigating the role of GHS-R1a dimerization and developing strategies to modulate these interactions therapeutically [1, 2].

References

[1] Giorgioni, G., et al. (2022). Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor. *Journal of medicinal chemistry*, *65*(5), 3796–3830. PMC8883476

[2] Müller, T. D., et al. (2020). Ghrelin signaling: GOAT and GHS-R1a take a LEAP in complexity. *Endocrinology*, *161*(7), bqaa061. PMC7299083