Profiling Hits

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

Unity resulted in 4234 hits. After application of several filters and clustering of the remaining 1975 molecules, compounds from 18 of the 27 clusters were screened in Xenopus oocytes. One compound with an IC50 of 5.6pM belonged to a new class of Kvl.5 blockers and exhibited a favorable pharmacokinetic profile. After further optimization, compound 73 (IC50 = 0.7pM Fig. 16.9) resulted, with good oral bioavailability in rats [145]. 

In the right-hand section, N-ethylation of the aniline nitrogen was optimal, while shifting the methyl to the 4-position increased activity. This, combined with fluorination at the m-position, afforded (23b) as the most potent compound of this series. Since the pharmacokinetic properties of (23b) were not disclosed, it is not clear if manipulation of the hit compound led, apart from an increase in potency, to a corresponding improvement of the pharmacological profile. 

AstraZeneca (year 2000) Generic lead target profile for progressing HTS hits to leads ... 

L-type calcium channels (voltage-gated calcium channels L-subtype) Similarity to Diltiazem and a second ligand. ZINC db ( 50 K commercially available subset screened but most filtered to achieve desired PK profile using VolSurf). SHOP similarity, and feature-presence filtering down to 36 compounds 7 hits 18 tested, active in a vasorelaxant assay and some had novel structures. [67]... 

From an early drug discovery and hit triage perspective, a simplification that is typically made is to focus initially on CYP metabolism that occurs in the fiver. This simplification is appropriate for the majority of compounds - some compounds will be cleared by other mechanisms, but it is generally assumed that they must be relatively stable to CYP metabolism to achieve a desirable PK profile. 

At the outset of a lead identification effort, it is imperative to establish specific criteria for potency, selectivity, ADME properties, etc. to generate a desired lead profile. This profile serves to guide the lead identification efforts based on the initial characterization of the hits. 

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