Structure-selectivity relationships synthesis

Itoh Y et al (2007) Design, synthesis, structure-selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors. J Med Chem 50(22) 5425-5438... 

Lopez-Rodriguez ML et al. (1996) Synthesis and structure-activity relationships of a new model of arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-l-yl]methyl]-1, 3-dioxoperhydroimidazo[l,5-alpha]pyridine a selective 5-HTlA receptor agonist. J Med Chem 39(22) 4439-4450... 

The third step is to optimize the lead molecule through iterative chemical synthesis and biological testing, aiming to obtain molecules with the required potency (typically nanomolar), selectivity, bioavailability, and DMPK (drug metabolism and pharmacokinetics) properties. This step usually requires considerable time and resources usually the synthesis of hundreds of compounds is needed to deduce a robust SAR (structure-activity relationship). Such resources can be considerably reduced and the... 

Thus, cholinergic receptor classification can be considered in terms of three stages of development. Initially, Dale [2] distinguished nicotinic and muscarinic receptor subtypes with crude alkaloids. Then, chemical synthesis and structure-activity relationships clearly revealed that nicotinic and muscarinic receptors were heterogeneous, but chemical selectivity could not come close to uncovering the true diversity of receptor subtypes. Lastly, analysis of subtypes came from molecular cloning, making possible the classification of receptors on the basis of primary structure (Fig. 11-2). 

Wermuth, C. G., Bourguignon, J.-J., Schlewer, G Gies, J.-P., Schoenfelder, A., Melikian, A., et al. (1987) Synthesis and structure-activity relationships of a series of aminopyridazine derivatives of y-aminobutyric acid acting as selective GABA-A antagonists../. Med. Chem. 30, 239-249. 

Lopez-Rodriguez, M.L., Morcillo, M.J., Fernandez, E., Porras, E., Murcia, M., Sanz, A.M. and Orensanz, L. (1997) Synthesis and structure-activity relationships of a new model of arylpiperazines. 3.2-[o-(4-Arylpiperazin-l-yl)alkyl]perhydropyrrolo-[l,2-c] imidazoles and -perhydroimidazo[l,5-a] pyridines study of the influence of the terminal amide fragment on 5-HTiA affinity/selectivity. Journal of Medicinal Chemistry, 40, 2653—2656. 

Knowledge of structure-activity relationships has permitted the synthesis of sympathomimetics that display a high degree of selectivity at adrenoceptor subtypes. 

Direct modification has also been applied to the synthesis of fluoro-substituted amikacin (Scheme 4.21). Utilizing the metal-chelating protocol and the steric hindrance of 5-OH, fluorination was carried out selectively at the 5-OH. Two compounds (132 and 133) were found to have similar trends of antibacterial activity (Table 4.11). However, the activities of amikacin, 132 and 133, against E. coli (ANT(2")) were found to be much higher than those reported in Table 4.10 regardless of the sites of deoxygenation. We believe that the results from Table 4.11 may better explain the trend of structure activity relationship... 

Richardson TI, Qmstein PL, Briner K, et al. Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor. / Med Chem 2004 47 744-55. 

The studies presented here along with helical bundle approaches provide a vehicle for exploring in detail the structure-function relationships of ion channels through the synthesis of artificial molecules with simple and controllable structural features. The control of electric fields at the ion-selective filter may elucidate the molecular mechanism of K /Na and NaflCa selectivities. Variation of the critical pore size by synthetic elaboration may give direct clues on the magnitude of conductance and discrimination of metal ions. Further studies on voltage depend-... 

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