Clinically Anchored GPCR Drug Discovery: Translational Lessons from Success, Failure, and Post-Approval Reassessment

Background/Objectives: G protein-coupled receptors are a productive drug target family, yet clinical performance varies widely across rare, immune-mediated, pain, and thromboinflammatory diseases. We aimed to construct an explicit, stage-gated framework that makes translational prioritisation auditable and to examine whether it distinguishes clinically successful from unsuccessful programmes. Methods: This narrative, clinically anchored review included programmes with a stated human-disease rationale, Phase 2 or later clinical experience or a regulatory decision, and publicly accessible primary or regulatory documentation; evidence was considered through 7 August 2026. The cases spanned rare disease, immune-mediated inflammation, pain, and thromboinflammation. Thirteen programmes were reviewed, and eleven were entered into a retrospective five-axis scorecard covering human-disease anchoring, receptor pharmacology, modality and pharmacokinetic/pharmacodynamic feasibility, biomarker-to-endpoint readiness, and durability. Each axis was scored 0–2, weighted to 100 points, and subject to predefined hard-stop rules. Results: Established successes scored 80–100 points, whereas failed programmes scored 30–48. PAR4 scored 57.5 and therefore fell in the stop-and-rework band; avacopan scored 80 before approval but now triggers an Axis 5 hard stop. Equal weighting preserved the classifications of established successes and hard-stop failures but shifted PAR4 to 60.0, demonstrating sensitivity of a borderline programme to the weighting scheme. The scorecard localized failures mainly to redundancy, biomarker–endpoint disconnect, or durability/evidence-integrity gates. Conclusions: The framework is an explicit prioritisation aid, not an externally validated predictive model. Its main value is to identify missing evidence and non-compensable weaknesses; prospective independent validation, including inter-rater reliability testing, is required before portfolio use.