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Examples Metformin Dosage Immediate release Initial: 500 mg once or twice daily OR 850 mg once daily Maximum: 2,550 mg daily (dosages above 2,000 mg daily are typically administered in three divided doses) Extended release Initial: 5001,000 mg once daily Maximum: 2,000 mg daily Possible side effects include: Gastrointestinal: diarrhea, nausea, and/or abdominal discomfort Vitamin B12 deficiency (and elevated homocysteine) Testosterone reduction (blood tests can measure this and natural testosterone prescription creams may be considered) Oral glucagon-like peptide-1 (GLP-1) receptor agonist Primary mechanism(s) of action Enhance incretin signaling to increase glucose-dependent insulin secretion, reduce post-prandial glucagon, and delay gastric emptying (resulting in reduced after-meal glucose levels and increased satiety) Examples Semaglutide (Rybelsus) is the only approved medication in this class as of early 2022

Figure 10 In addition to the sulfonamides, e.g., 40 and 41 , the spiro-oxindole dihydroquinazolinone derivative 42 was identified in the screening campaign and subsequently a large series of related analogues were made, e.g., by applying rapid MW-assisted reactions and thereafter examined as IRAP inhibitors in bioassays (Engen et al., 2020) (Figure 10)