Rings in “Lead-like Drugs”

Abstract

Background: Lead-like drugs, which present molecular weight (MW) < 300 Da, occupy an important space in the pharmaceutical area. Most of these small molecules have ring systems, which are important for their physicochemical properties and biological activity. Previous studies have evaluated ring systems in historic drugs or drug candidates in clinical trials. Objective: The purpose of this work was to analyze ring systems, focusing on this group of drugs with MW < 300 Da, to obtain specific insights. Methods: The lead-like drugs (n = 219) were obtained from previous publications and the new FDA drug approvals were obtained after that and analyzed using the DataWarrior software. Results: Most of the lead-like drugs (> 92%) present one or two rings, with the benzene ring and heterocycle ring systems being predominant. Pyridine, imidazole, piperidine, 4,5-dihydro-1Himidazole, and indole are the most frequent heterocycles in this set. The higher frequency of the 4,5- dihydro-1H-imidazole ring in the lead-like drugs is worth noting, as it is not observed in other drugs. The introduction of new rings has been similar in the lead-like drugs and the historic drugs, over the years; an example would be the 1,2,4-thiadiazinane 1,1-dioxide, which is present in the antimicrobial Taurolidine, a lead-like drug, and engages in the metabolic activation of the drug. Conclusion: In general, the ring systems in the lead-like drugs appear to follow similar patterns to the historic drugs. Additionally, few new ring systems are being introduced, which suggests that this is an emergent field to be explored in drug discovery.