Pfizer PF-05190457, commonly referred to as PF-5190457 in published studies, is an orally bioavailable, potent, and selective inverse agonist of the ghrelin receptor GHS-R1a. Originally developed as a clinical candidate, it has been investigated for studying ghrelin signaling in alcohol use disorder and metabolic regulation. The PF-5190457 molecular structure belongs to the spiro-azetidino-piperidine series developed during the optimization of selective GHS-R1a inverse agonists. PF-5190457 has a molecular weight of 512.24 g/mol and a calculated cLogP of 2.93. The compound is supplied at 95% purity, with purity validated by NMR and/or LCMS methods, under an agreement with Pfizer Inc.
Application of PF-5190457
PF-5190457 is used mainly as a tool for probing the ghrelin system's role in alcohol use disorder, since it was the first GHS-R1a inverse agonist to reach clinical testing for this indication. Its dual mechanism, inhibiting the receptor's constitutive activity while also blocking acyl-ghrelin activation, makes it useful for distinguishing inverse agonism from simple receptor blockade. A clinically observed nuance adds research value: tachyphylaxis developed only at peripheral GHS-R1a sites while central anti-craving effects persisted, making PF-5190457 relevant for studies separating peripheral from central receptor pharmacology, and it also serves as the parent compound for characterizing its major metabolite, PF-6870961, in biased-signaling research.
In Vitro
PF-5190457 potently and selectively inhibits GHS-R1a-induced inositol phosphate accumulation, confirming its activity as a competitive antagonist of acyl-ghrelin. Its major hydroxy metabolite, PF-6870961, is less potent in this assay but more potent at inhibiting GHS-R1a-mediated β-arrestin recruitment, pointing to biased inverse agonism between the two pathways.
In Vivo
In rats, PF-5190457 did not alter alcohol's effects on locomotor activity or the loss-of-righting reflex, and alcohol co-administration did not change blood PF-5190457 concentrations. In a Phase 1b human study, heavy drinkers receiving PF-5190457 alongside alcohol had only mild-to-moderate adverse events, and the 100 mg twice-daily dose reduced alcohol craving during a cue-reactivity procedure, with parallel shifts in acyl-to-total ghrelin ratio and IGF-1.
Biochemical and Physiological Actions
The PF-5190457 chemical structure enables interaction with GHS-R1a through two linked mechanisms: it lowers ligand-independent constitutive signaling and competitively blocks binding of acyl-ghrelin, the receptor's endogenous agonist. Because GHS-R1a is expressed both peripherally and in central reward circuitry, peripheral blockade appears to desensitize faster than central blockade, which helps explain why anti-craving effects persisted even as peripheral responses declined.The PF-5190457 structure therefore provides a useful reference for mechanistic studies of GHS-R1a inverse agonism and receptor pharmacology.
Features and Benefits of PF-5190457
For labs studying ghrelin signaling and alcohol use disorder pharmacology, PF-5190457 offers:
- a dual inverse agonist/competitive antagonist mechanism at GHS-R1a, useful for dissecting constitutive versus ligand-driven receptor activity;
- clinical-stage validation as the first GHS-R1a inverse agonist tested in heavy drinkers, with published safety and pharmacodynamic data;
- well-documented PF-5190457 molecular weight, supporting compound identification and analytical reference use;
- CAS 1334782-79-4 at 95% purity with NMR/LCMS-verified quality control, supplied under agreement from Pfizer Inc.
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