What first-generation oral GLP-1 drugs teach about designing the next ones
- Reviews nonpeptidic GLP-1 receptor agonists that reached the clinic, including danuglipron, lotiglipron, DA-302168S and orforglipron, as case studies of how each solved the oral-delivery problem.
- Notes the design challenges these first-generation molecules still leave open.
- Proposes next-generation approaches: peptidomimetic design, multi-target agonists, and exploiting orthosteric-allosteric cooperativity.
- Covers practical aspects such as screening cascades, preclinical species choice, formulation and early safety assessment, with relevance to other difficult GPCRs.
💡 Points
Four clinical chemotypes, four different answers to the same problem: a class B GPCR built to bind a large peptide. What I want from a review like this is the SAR logic behind each survivor. Orthosteric-allosteric cooperativity is the idea I'd chase, since it could loosen the potency-versus-permeability tradeoff. Whether it holds up depends on the screening cascade and species choice, which is where programs usually stumble.