Potency selectivity

Lead structure According to Valler and Green s definition a lead structure is a representative of a compound series with sufficient potential (as measured by potency, selectivity, pharmacokinetics, physicochemical properties, absence of toxicity and novelty) to progress to a full drug development program [12]. 

The term virtual screening or in silica screening is defined as the selection of compounds by evaluating their desirability in a computational model [17]. The desirability comprises high potency, selectivity, appropriate pharmacokinetic properties, and favorable toxicology. 

Receptor Natural agonists (order of potency) Selective agonists... 

Experimental data (potency, selectivity, ADME, safety, physchem properties)... 

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. 

Generally, all of the assays used for characterization of hits in terms of potency, selectivity, function, and or cellular activity will continue to be used to characterize new compounds synthesized to identify leads. However, additional assays will normally be added to characterize compound selectivity more fully, to provide additional evidence that compounds are acting on the desired pathway and by the desired mechanism. 

Armour CCR5 Potency, selectivity, physicochem, ADME, PK Modeling of CYP 2D6 [61]... 

The use of fluorine to modulate properties including potency, selectivity, pharmacokinetics, and toxicity has have been highlighted. Fluorine has also been suggested as a potential bioisosteric replacement for a number of functional groups, examples of which are presented in the final section. 

Meyers MJ, Sun J, Carlson KE, Marriner A, Katznellenbogen BS, Katzenellenbogen JA (2001) Estrogen receptor-/ potency-selective ligands structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 44 4230-4251... 

The past 3 years have seen tremendous advances in both the design of Cat K inhibitors and in our understanding of the effect of Cat K inhibition on bone remodeling. The structural diversity of Cat K inhibitors has expanded considerably from simple peptidomimetics to non-peptidic derivatives and even non-covalent inhibitors. The potency, selectivity and pharmacokinetic properties of key compounds are very attractive and seem well-suited to further development. The disclosure of clinical validation of the effect of Cat K inhibition on bone mineral density, plus the provocative data suggesting a decoupling of bone resorption and bone formation provides a compelling framework for further development of Cat K inhibitors for the treatment of osteoporosis. 

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

ErbB inhibitors in development differ in several aspects, including potency, selectivity, and mechanism of inhibition. Fortunately, there are data that compare erlotinib, gefitinib, lapatinib, canertinib, HKI-272, and BIBW 2992 directly in enzymatic and cellular studies, as shown in Tables 2 and 3 [89,95]. 

B-score Biological profile score based on potency, selectivity, and toxicity of a compound. 

In Figs. 8-10 one can see that the distribution of average potency, selectivity, and average efficacy/toxicity ratio is exactly as one would desire. One can conclude that list 1, the highest priority list, contains the most efficacious compounds based on the degree of testing performed so far. 

There are several natural milestones during drug development, and although there are differences between companies, both in the number and in the names of the milestones, these differences are quite small. The first milestone is the selection of a compound in the drug discovery phase for development. In the past this decision was exclusively based on the pharmacology (potency, selectivity) of the compound. Since there is now greater awareness that compounds with attractive pharmacological properties may fail later because of poor solubility or extensive metabolism, the physical chemistry, preliminary PK and metabolism characteristics of the... 

In the previous examples, random and targeted libraries are used to discover leads. Optimization libraries are employed when lead structures have already been identified, serving to improve the potency, selectivity, or other characteristics of the molecule. 

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