Potency relationships

Because the goal of hit triage is to identify chemical series that hold promise for further optimization, an approach to characterize the ADME properties of a series, not just individual compounds is often useful. Where possible, characterizing the structure-ADME property relationship, in much the same way that a structure-potency relationship is defined, can be valuable for assessing the probability that a given structural series can be successfully optimized. The goals of this ADME property characterization are twofold (1) to identify specific structural features that may be liabilities (benefits), and (2) to identify general structure-ADME property correlations. 

Several assays have been described by investigators in the field and they are used for different purposes. Assays involving purified Cox-1 and Cox-2 are used for convenience and speed or to obtain an estimate of the relative intrinsic potency and selectivity of inhibitors. Selectivity based on intrinsic affinity for the catalytic site permits the development of structure-potency relationships that one can interpret in terms of structural features of the inhibitors and the catalytic sites of the target enzymes (Bayly et al., 1999). Cell-based assays are used to determine whether the inhibitors can enter cells and inhibit Cox, as well as to determine inhibitor potency in a more biologically relevant environment than provided by purified enzyme assays. At Merck, CHO cell lines that overexpressed human Cox-1 or Cox-2 were developed and used for screening cell-based assays (Kargman et al., 1996). 

Potency relationships among a series of N-snbstituted norpethidines... 

Vracko, M. (1997). A Study of Structure-Carcinogenic Potency Relationship with Artificial Neural Networks. The Using of Descriptors Related to Geometrical and Elecronic Structures. J.Chem.Jnf.Comput.Sci., 37,1037-1043. 

T. D. Egan, K. T. Muir, D. J. Hermann, D. R. Stanski, and S. L. Shafer, The electroencephalogram and clinical measures of opioid potency defining the EEG-clinical potency relationship ( fingerprint ) with application to remifentanil. Int J Pharm Med 15 1-9 (2001). 

That the lipid solubility versus anesthetic potency relationship is not above criticism has been intimated for a number of years by a number of authors. Summaries of the relevant facts and comments are found in the reviews of Halsey and Kaufman . It is only since 1974, however, that the possible importance of polar interactions has become a target of intense discussions. General anesthetics have widely different chemical structures and it has never been possible to classify them on chemical grounds. Xenon, nitrous oxide, ethylene, cyclopropane, ether, chloroform, C Fg, SFg, CFj—CHClj, CFj-CHClBr (halothane), CHjOCF.CHCf, (methoxyflurane) can all exert anesthetic action. (This aspect will be discussed in more detail in the next section). Looking at the formulas of these different molecules it is hard to believe that they all associate with the same site and with the same type of forces. A series of observations have been made in recent years that substantiate this scepticism. 

Vracko, M. (1997) A study of structure-carcinogenic potency relationship with artificial neural networks. The using of descriptors related to geometrical and electronic structures./. Chem. Inf. Comput. Sci., 37, 1037-1043. 

The stage was then set for Ahlquist s (1948) classic experiments leading to the proposal of a and 3 adrenoceptors. The research was based on sensitivities to NE and EP and related substances. In essence, he discovered an inverse potency relationship between producing excitation in smooth muscles (peripheral vasoconstriction, uterus, ureter) and intestinal smooth muscle inhibition—Set A—and the production of vascular inhibition (vasodilation) and of the uterus, and cardiac excitation—Set B. The experimentation utilized dogs, cats, and rabbits as well as isolated animal tissues. The amines tested showed a decreasing potency in the order listed for Set A effects, and the opposite for Set B effects ... 

Relative potency relationships in various experimental procedures for... 

The analyses for structure-inhibitory potency relationships indicated that the improvement of inhibitory potency against plant PDHc required an optimal combination of R R, R, and Y . As shown in Scheme 7.4, when 2,4-Cl2 as Y are kept constant, inhibitory potency of the compound could be greatly enhanced by the chemical modification of R, R and R in the phosphoms-containing moiety. Especially the conversion of phosphonate esters to their salts could make great improvement in inhibitory potency against plant PDHc. Thus IIB-2 was found to exhibit the best inhibitory potency against rice PDHc. 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Structure—Activity Relationships. In spite of the considerable synthetic and bioassay effort involved in estabhshing the thyromimetic potency of thyroid-hormone analogues, more than 100 compounds have been studied (Table 2). The main stmctural requirements for thyromimetic activity can be summarized as follows (6,12—16). 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

It is a hallmark of the structure activity relationships of the corticoids that the effects of structural modifications that lead to increased potency are usually additive. The fact that more than half a dozen such modifications each lead to increased potency opens ever new possibilities for combinations and permutations. Meclorisone dibutyrate (74) thus combines the known... 

The generally accepted structure-activity relationships developed in the early work in the quinolone series held that the N-1 substituent needed to be small and aliphatic. This picture was upset in a dramatic way with the discovery of the excellent potency and antimicrobial spectrum of difloxacin (45) and its congeners in which the substituent on N-1 is an aromatic ring. The synthe-... 

Receptor density has disparate effects on the potency and maximal responses to agonists. The operational model predicts that the EC50 to an agonist will vary with receptor density according to the following relationship (see Section 3.13.3)... 

Drug-Receptor Interaction. Figure 2 Relationships between affinity and efficacy with different agonist response patterns, (a) For partial agonists, differences in maximal responses between agonists relate to differences in efficacy. Differences in the location parameter of the concentration-response curve (potency) indicate differences in affinity, (b) For full agonists, differences in potency indicate differences in either affinity, efficacy or both. 

Schild analysis is a very powerful method to quantify the potency of a competitive antagonist and to test whether the blockade of response by a molecule is consistent with simple competitive antagonism. Devised by Arunlakshana and Schild (1959), it is based on the principle that the antagonist-induced dextral displacement of a dose-response curve is due to its potency (Keq value, affinity) and its concentration in the receptor compartment. Since the antagonism can be observed and the concentration of antagonist is known, the Keq (denoted KB for antagonist) can be calculated. Die relationship between antagonism and concentration must be log-linear with a unit slope to adhere to true competitive kinetics. 

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