Historical compounds

The two most frequently studied compounds with T-type calcium channel antagonist properties are ethosuximide 1 and mibefradil 3. However, the modest potency of ethosuximide ( 200 pM) [48] and the poor selectivity of mibefradil [49] make these compounds suboptimal tools for the investigation of these channels. Guided by a pharmacophore model [50], several analogs of 3 were prepared. Compound 4 represents the most potent compound identified (IC50 8 nM, patch-clamp assay) with good selectivity over the L-type calcium channel [51], Compound 4 showed a modest brain-to-plasma ratio (0.25) after oral dosing to rats at 50 mg/kg. However, no in vivo efficacy assay results have been reported with this compound. 

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Historically, compounds of graphite have been placed in three categories, depending on the strength of interaction between reacting species and graphite ... 

As some of the toxicity observed with DPP-8/9 inhibitors 4 and 7 in predinical species suggested a potential immune system role, we hypothesized that the immunological effects observed with historical DPP-4 inhibitors [14] might be due to inhibition of DPP-8/9 instead of DPP-4 as initially reported. Sure enough, when these historical compounds were assayed at DPP-8/9 and DPP-4, they possessed more potent intrinsic inhibition at DPP-8/9 than at DPP-4 [20]. Furthermore, we demonstrated that DPP-8/9 inhibitor 7 is able to attenuate proliferation and IL-2 release in human in vitro models of T-cell activation, while a selective DPP-4 inhibitor does not. Recent tissue distribution studies also suggest a role for DPP-8 in the immune system [25]. 

One of the most powerful uses of BioPrint is to provide a basis for understanding and learning from past clinical attrition. This is accomplished by systematically prohling historical compounds in the BioPrint assays and using the BioPrint data set as context in which to identify patterns of in vitro activity associated with chemical series, with therapeutic target activity, and with clinical adverse effects. BioPrint allows data from proprietary compounds to be put in context with analogous data on nearly every compound that has succeeded (or not) in getting market approval. 

Spatial arraying has been used traditionally for the assaying of historic compound collections. As the identity of the molecule is correlated to position in the array, this approach carries the least challenge for stmctural assigmnent for active array positions. As an additional aspect to ease the implementation of arrayed libraries, arrayed libraries are commonly handled as solutions. As most biological assays are based on homogeneous test systems, providing the libraries in solution is the obvious... 

For lead finding, the use of chemical compound collections and combinatorial libraries is indispensable to every pharmaceutical company for a timely and efficient discovery of novel bioactive entities [5]. Until recently, most attention was paid only to internal historic compound collections, maintained over several years of medicinal research [6]. Flowev-er, those libraries typically contain a limited number of structural classes as the result of past research projects which focused on biological activity islands .Today there is a growing interest in techniques that expand structural and - even more important - biological diversity, this perhaps being accomplished by the direct acquisition of an external compound collection, or by the use of internal or external synthesis capacities [7]. 

Fig 12 43. Distribution (rfrmlecuiar weight, number of rotatabk bands and calculated partition coefficient for a number of early libraries synthesised at Glaxo Wellcome (libl-hb4), together with the corresponding distributions for the World Drug Index (wdi) and a set cf representative historical compounds (rep)... 

Besides the established sources of obtaining diversity, mainly from historic compound collections, publicly or commercially available compound libraries, and natural products, novel approaches toward expanding diversity have been described in the recent literature. 

Historic compound collections no doubt have the advantage when it comes to quality, availability, and comprising chemically interesting and sometimes still proprietary structures, but by definition newer companies won t have them. And even the companies that do are prodigious purchasers of commercial screening compounds. 

Scientists at AstraZeneca shared their experiences with their historical compound collections, which prompted them into defining a number of selection criteria in order to filter out compounds of little value for the hit-to-lead process [27]. Subsequently, this led to a compound collection enhancement program. 

Historically compounds such as CDEC were important to show that herbicidal activity could be found in compounds where the R groups were alkyl. Unfortunately, toxicology problems were found with the better herbicidal compounds. 

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