Profiling primary assay

Chemical Leads Primary Assay IC50 < 1 pM Selectivity Assay 10-fold selectivity Cellular Assay IC50< 1 pM Acceptable in vitro ADME Acceptable PK Profile Potentially patentable... 

A demonstrated increase in potency in the designated primary assay as defined by the project and in adequation with target candidate profile (TCP). Evidence of cellular activity in a functional assay commensurate with mechanism of action. 

At lead selection, after which typically more chemistry effort is invested, the selected compounds can be profiled in a broader (secondary) panel of assays, hopefully confirming the selective nature of the leads. If this is the case, spot checking in the primary panel through the optimization phase may be sufficient to ensure selectivity is retained while the required potency at the primary target is achieved. If the selected leads are still rather promiscuous, or certain individual unwanted liabilities remain, these should be monitored by testing in the primary panel (or in additional individual assays) and improved upon during lead optimization. Tfie broader panel can then be applied again to the selected development candidates for a final check and these may even be extended further to additional specialized panels for added security. 

IFN-a Family. There are 14 human genes that comprise the IFN-a family. These genes generally encode mature polypeptides with either 165 or 166 amino acids and have a 15% to 25% variation in primary amino-acid sequence. Minor variants consisting of one or two amino-acid differences account for multiple alleles. Thirteen separate proteins are expressed from these 14 genes (Table 7.1), each with a different profile of antiviral and antiproliferative activity [40,41]. Evidence for cell specificity of IFN-a subtypes has been reported. For example, IFN-al has greater antiproliferative effects on B-cell neoplasms, whereas IFN-a2 is more specific for other malignancies [42]. When assayed on human cells, IFN-al has less antiviral activity than IFN-a2 [43]. Nevertheless, IFN-al has potent antiviral activity in bovine-, feline-, and primate-derived cells [44]. Fur-... 

During the first half of the century, there was virtually an exclusive reliance on animal testing as the primary model for drug discovery and development. New chemical entities were administered to rodents in the primary screen assay, and the appropriate responses were monitored for indications of therapeutic potential. Compounds meeting the appropriate potency and efficacy criteria were promoted to more diverse and sophisticated animal models to characterize their pharmacological profile. The responses that were monitored included blood pressure (hypotensives), latency to respond to painful stimuli (analgesics), attenuation of seizure propensity (antiepileptics) and other responses that were intuitively and pharmacologically valid indicators of medicinal potential or toxicity. Some of these methods were semiautomated and quite sophisticated for their time, particularly for cardiovascular indications [1]. 

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