Is there a difference between leads and drugs? A historical perspective

To be considered for further development, lead structures should display th e following properties: ( 1) simple chemical features, amenable for chemist ry optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metabolism, and e xcretion (ADME) properties. There are two distinct categories of leads: tho se that lack any therapeutic use (i.e., "pure" leads), and those that are m arketed drugs themselves but have been altered to yield novel drugs. We hav e previously analyzed the design of leadlike combinatorial libraries starti ng from 18 lead and drug pairs of structures (S. J. Teague et al. Angew. Ch cm., Int. Ed. Engl. 1999, 38, 3743-3748). Here, we report results based on an extended dataset of 96 lead-drug pairs, of which 62 are lead structures that are not marketed as drugs, and 75 are drugs that are not presumably us ed as leads. We examined the following properties: MW (molecular weight), C MR (the calculated molecular refractivity), RNG (the number of rings), RTB (the number of rotatable bonds), the number of hydrogen bond donors (HDO) a nd acceptors (HAC), the calculated logarithm of the n-octanol/water partiti on (CLogP), the calculated logarithm of the distribution coefficient at pH 7.4 (LogD(74)), the Daylight-fingerprint druglike score (DFPS), and the pro perty and pharmacophore features score (PPFS). The following differences we re observed between the medians of drugs and leads: Delta MW = 69; Delta CM R = 1.8; Delta RNG = Delta HAC =1; Delta RTB = 2; Delta CLogP = 0.43; Delta LogD(74) = 0.97, Delta HDO = 0; Delta DFPS = 0.15; Delta PPFS = 0.12. Lead structures exhibit, on the average, less molecular complexity (less MW, le ss number of rings and rotatable bonds), are less hydrophobic (lower CLogP and LogD(74)), and less druglike (lower druglike scores). These findings in dicate that the process of optimizing a lead into a drug results in more co mplex structures. This information should be used in the design of novel co mbinatorial libraries that are aimed at lead discovery.