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 sp3 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.