What Happens in Successful Optimizations? A Survey of 2018–2024 Literature

Molecular properties of 478 start compounds to candidate optimization pairs from the 2018–2024 literature are analyzed by target, target class, start compound origin, mechanism, disease area, and route of administration. 86.3% of oral candidates are Ro5 compliant. All properties tend to converge in optimization toward a candidate “norm”. Target class property differences persist in the starting compounds and candidates. Average lipophilicity does not change, and the increase in average molecular weight of 81 Da is associated with a potency increase. Prominent underlying factors include increased complexity, counts of sp 3 carbon atoms, H-bond acceptors, and natural product fragments, and a decreased number of carboaromatic rings. The occurrence of common ring systems increases in optimization, and on average, 70% of the starting compound structure is retained in the candidate. An extensive selection of illustrative optimization examples is presented, “lead-likeness” as a desirable attribute of starting compounds is appraised, and trends in optimization strategies are discussed.