Lead molecules

The identification of suitable lead molecules is a crucial process with important implications for success in drug development. There is a growing common under-... 

A benzodiazepine template was also reported by researchers at GlaxoSmithKline [85]. The lead molecule GW405212, (40), was identified from a 1,296-member library of 1,4-benzodiazepines prepared on Tentagel beads and screened initially in pools of 30 against CHO cells expressing the human oxytocin receptor. It is a highly potent inhibitor of oxytocin binding with a K of 8nM [86]. However, all attempts to improve the pharmacokinetic properties of this molecule were unsuccessful. It appears that the functionality responsible for the oxytocin activity is distributed around the periphery... 

Fig. I The desired attributes of a lead molecule. Often, molecules identified by any screening strategy might satisfy optimal criteria for only a subset of these attributes and most laboratories would proceed with a medicinal chemistry campaign banking on improving the rest in a subsequent lead optimization phase...

The third step is to optimize the lead molecule through iterative chemical synthesis and biological testing, aiming to obtain molecules with the required potency (typically nanomolar), selectivity, bioavailability, and DMPK (drug metabolism and pharmacokinetics) properties. This step usually requires considerable time and resources usually the synthesis of hundreds of compounds is needed to deduce a robust SAR (structure-activity relationship). Such resources can be considerably reduced and the... 

To most effectively search chemical libraries for diverse lead molecules, enzyme assays used for HTS must take into account the conformational dynamics of enzyme catalysis and the physiological context of enzyme action in vivo. 

The goal of HTS should be to identify the broadest diversity of lead molecules, with diversity defined in terms of both chemical structure and inhibition modality. 

As we stated above, there is a risk involved in the use of the Cheng-Prusoff relationships for SAR studies, as it is possible that structural alterations of the lead analogues could change the inhibition modality. This can be check from time to time for compounds that represent the greatest structural excursions from the lead molecule. Additionally compounds that are destined for progression into cellular and animal models should have their inhibition modality and affinity confirmed by running the more comprehensive studies discussed in Section 5.3. 

The renaissance of the Biginelli MCR can be attributed to the obtained pyrimidine derivatives, which show remarkable pharmacological activity. A broad range of effects, including antiviral, antitumor, antibacterial, anti-inflammatory as well as antihypertensive activities has been ascribed to these partly reduced pyrimidine derivatives [96], such as 9-117 and 9-118 (antihypertensive agents) [97] and 9-119 (ala-adrenoceptor-selective antagonist) [98] (Scheme 9.24). Recently, the scope of this pharmacophore has been further increased by the identification of the 4-(3-hydroxyphenyl)-pyrimidin-2-thione derivative 9-120 known as monastrol [98], a novel cell-permeable lead molecule for the development of new anticancer drugs. Monastrol appears specifically to affect cell division (mitosis) by a new mechanism,... 

Section 2 briefly outlines the identification of fragments where the optimisation is either not described, or only a limited amount of optimisation was achieved. Section 3 shows examples where lead molecules (<1 gM potency) were successfully derived from fragments. Finally, in Section 4 we give a commentary of key concepts, impacts and challenges for the field. 

Overall, several useful concepts emerge from these analyses. Different targets and routes of administration may require biased property distributions and screening libraries for successful lead optimization. This could influence the eventual chances of project success and should be taken into account early by project leaders. Once more, optimization focused on potency has been shown again to lead to larger molecules which increases the potential for poor ADME properties. The extent of any ADME issues would of course depend on the structure of lead molecule. Finally, larger, more lipophilic molecules historically have an increased rate of failure in the clinic. 

Systematic variation is also useful for optimizing certain properties (e.g., solubility, novelty, toxicity, or metabolic stability) of a lead molecule. The fragment optimization... 

Analytical methods are important not only in the development and manufacture of commercial biopharmaceutical drugs, they also play a vital role in the whole drug development life cycle. Drug discovery and preclinical research require development and application of analytical methodologies to support identification, quantitation, and characterization of lead molecules. It is difficult to perform a comparative potency assay on lead molecules if one does not know how much of each is going into the assay or how pure the molecule is. Analytical methods are typically developed, qualified, and validated in step with the clinical... 

Polymerization of fullerite was first obtained at ambient pressure by means of sample irradiation [456]. Visible or UV light leads molecules to link together in a covalently bonded fee structure. From x-ray diffraction data a 2 + 2 cycloaddition mechanism was proposed in which the van der Waals interactions are replaced by single covalent bonds between adjacent Ceo molecules [456]. More recent results indicate that linear chains with two square rings per molecule or branched chains with three square rings per molecule are obtained... 

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