Structure Activity Relationship SAR

The 4-ary 1-2,4-diketobutanoic acid class of IN inhibitors (also known as 1,3-diketo acids, or DKAs) was discovered independently by researchers from Merck and Shionogi, with patents from both groups published in the same year.13 From a random screen of 250,000 compounds, the Merck group identified DKAs as the most active IN inhibitors. Compound 7 was the most potent compound found in this screen (Table 1), completely inhibiting HIV-1 infection in a cell-based assay at a concentration of 10 pM.10 

The Merck group s efforts to find a more stable substitute for the DKA pharmacophore resulted in the design of 8-hydroxy-[l,6]naphthyridines such as compound 10,19 wherein the keto-enol-acid triad was replaced with a 1,6-naphthyridine ketone bearing a phenolic hydroxyl group. Further refinement of compound 10—replacement of the naphthyridine phenyl ketone with a 4-fluorobenzyl carboxamide and addition of a six-membered sulfonamide at the 5-position of the naphthyridine core—resulted in compound 11, the second IN inhibitor to reach the clinic.20 The discovery of liver toxicity in long-term safety studies of compound 11 in dogs led to the suspension of clinical development21 of this compound. 

A second IN inhibitor has reached Phase III clinical trials since the launch of raltegravir. Elvitegravir (13) is a dihydroquinolone carboxylic acid the monoketo acid motif of this series of inhibitors is proposed to mimic the keto-enol-acid triad of the DKA lead structures.24 Like raltegravir, elvitegravir is a specific inhibitor of HIV-1 strand transfer.25 

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The structure activity relationships ( SAR) of newly synthesized analogues of nucleosides, xanthine heterocycles, and nonxanthine heterocycles have been explored at the ARs. Potent and selective AR antagonists have been prepared for all four subtypes [3, 4], and selective agonists are known for three subtypes [1]. Thus, numerous pharmacological tools are available for in vitro and in vivo use (Table 2). Potent and selective A2b AR agonists are yet to be repotted, although several research groups have identified lead compounds. 

Most relevant for the affinity for A9-THC and analogs to CB-receptors are the phenolic hydroxyl group at C-1, the kind of substitution at C-9, and the properties of the side chain at C-3. Relating to the structure-activity relationships (SAR) between cannabinoids and the CB-receptors, many different modified strucfures of fhis subsfance group were developed and fesfed. The most important variations include variations of the side chain at the olivetolic moiety of the molecules and different substitutions at positions C-11 and C-9. One of the most popular analogous compounds of A9-THC is HU-210 or (-)-trans-ll-OH-A8-THC-DMH, a cannabinoid with a F,l-dimethylheptyl side... 

To establish the structure-activity relationships (SARs) of a set of molecules, a knowledge of the 3D structure is of great importance [2]. Thevand et al. recently (2004) reported the 3D structural analysis of tetrandrine using NMR and molecular modeling (the structure is shown in Fig. 1) [2]. They employed... 

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... 

This article summarises the general characteristics of a novel antibacterial target, peptide deformylase (PDF) and reviews the design, structure-activity relationships (SAR) and properties of known PDF inhibitors, including pre-clinical and clinical data for the most advanced members of this class. 

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... 

Another characteristic of PCP which has been studied with great interest over the last 5 years, is the ability of PCP to produce a discriminative stimulus in monkeys, rats, and pigeons. As discussed elsewhere in this volume, by Browne, the discriminative stimulus properties of PCP are shared not only by other members of the arylcycloalkylamine class, but by psychotomimetic benzo-morphans and substituted dioxolanes. The structure-activity relationships (SAR) within and between these classes are virtually identical to those found when studying the displacement of 3H-PCP from its binding site in rat brain membranes. This correlation... 

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. 

Predictions based on structure-activity relationships (SARs), including qualitative and quantitative mathematical models, and the use of read-across data from related chemicals. 

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. 

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