Structure-Activity Relationship SAR Studies

The in vivo antihistaminic activity results indicate that all test compounds protected the animals from histamine-induced bronchospasm significantly. Structural activity relationship (SAR) studies indicated that different alkyl substituents on the first position of the triazoloquinazohne ring exerted varied biological activity. 

One of the sources of the fuzziness surrounding these concepts may well be the implicit assumption in structure-activity relationship (SAR) studies that molecular structure contains (i.e. encodes) the information on the biological activity of a given compound. Such an assumption cannot be incorrect, since this would imply the fallacy of SAR studies. However, the assumption becomes misleading if not properly qualified to the effect that the molecular structure of a given compound contains only part of the information on its bioactivity. Indeed, what the structure of a compound encodes is information about the molecular features accounting... 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

Successful HTS campaigns often result in multiple lead pharmacophores that must be individually optimized through structure-activity relationship (SAR) studies. 

A rational approach to problems such as drug targeting to regions protected by P-gp, inhibition or even prevention of multidrug resistance in different organisms, and prediction of drug-drug interactions due to P-gp should become possible with reliable structure-activity relationship (SAR) studies. 

The design of the photoprobe is based on structure-activity relationship (SAR) studies if available. Ideally the photoprobe should be bioactive over the same range as its parent compound. The next step is to synthesize the bioactive photoprobe in radiolabeled form. Similarly, non-radioactive labels (primarily biotin) can also be attached via a linker arm [18]. 

Because rodent populations world-wide were becoming resistant to the widely used Warfarin-type anticoagulant poisons, a search was initiated to find a rodenticide with a different mode of action one that would be effective against these resistant rodents. This search led to the discovery of the toxic nature of a family of diphenyl amines which act as uncouplers of oxidative phosphorylation. A structure-activity relationship (SAR) study was undertaken to choose a derivative that would be both poisonous to rodents but still readily consumed by them. This approach led to the discovery of bromethalin,... 

Some structure-activity relationship (SAR) studies have been performed on specific ciasses of ciiemicals, including fluoroquinolones, quinine derivatives, pyrroles, thiophenes and polycyclic aromatic hydrocarbons (PAHs). 

In addition to the synthetic challenge of natural cyclic peptides, these compounds are often isolated in very low yields and thus their structure cannot always be determined without ambiguity. Consequently, total synthesis represents the safest way to prove their constitution, configuration, and even biological activity, since frequently this results from highly active minor contaminants. 10-12 Moreover, synthesis of the natural compounds allows for structural variations as required for structure-activity relationship (SAR) studies to identify the important pharmacophores and their orientation in space. Herein the reader is not provided with a comprehensive overview of the vast list of different natural cyclic peptides, but rather directed to comprehensive reviews. 1,13 Nonetheless, some important and characteristic representative members will be reported in the context of the synthetic methods. 

Major advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives appeared in 1999. Solid-phase combinatorial chemistry of benzimidazoles and tiiazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. In medicinal chemistry, synthesis and structure-activity relationship (SAR) studies utilizing these core structures have been exploited heavily. The physical organic chemistry of pyrazoles and imidazoles continue. 

Rong, F., Chow, S., Yan, S., Larson, G., Hong, Z., Wu, J. (2007) Structure-activity relationship (SAR) studies of quinoxalines as novel HCV NS5B RNA-dependent RNA polymerase inhibitors. Bioorg Med Chem Lett 17,1663-1666. 

Structure-activity relationship (SAR) studies including qualitative and quantitative SAR. 

In addition to their potential as antitumor agents, acetogenins have great potential as natural "organic" pesticides (Mikolajczak et al., 1988,1989 McLaughlin et al., 1997). Bullata-cin (1) and trilobacin (3) (see Figure 13.1) were more potent than rotenone, a classic complex I mitochondrial inhibitor, in a structure-activity relationship (SAR) study using yellow fever mosquito (YFM) larvae (He et al., 1997). 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

Structure-activity relationship (SAR) studies In this series of tetrahydrobenzazepines ( 5) indicate that the 1-phenyl, or substituted phenyl, group contributes significantly to the DA receptor agonist properties of these compounds (13, 14). As the 1-phenyl substituent in I-III provides these molecules with an asymmetric center, separation and study of the enantiomers was of particular Interest. 

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