Side-chain modification, structure-activity relationship

In designing studies of the structure-activity relationships of MDMA and related substances, there are at least three areas for structural modification. First, the nature of the amine substituents can be varied other N-alkyls can be studied, or the nitrogen can be incorporated into a ring system. A second point for structural modification is the side chain. As already demonstrated, the alpha-methyl can be extended to an alpha-ethyl. Other modifications of the side chain would include incorporation into a variety of ring systems, or a,a-dialkylation. Finally, the nature and location of the ring substituents can be modified. 

The discovery of BB-3497 was the result of screening a proprietary library for potential metalloenzyme inhibitors at the British Biotech Pharmaceutical Co. Ltd. [73]. This compound was originally prepared in a nonstereoselective manner and its stereochemistry was assigned on the basis of matrix metal-loprotease (MMP) inhibitory activity. The asymmetric synthesis of BB-3497 and the establishment of its stereochemistry by small-molecule X-ray crystallography was later reported by Pratt et al. [83]. Further structure-activity relationship studies of BB-3497 with respect to the modification of the P2 and P3 side chains [84] and metal binding group [85] were later reported by the scientists at British Biotech. These studies revealed that none of the... 

Structure/activity relationships among these,the ethanolamine series of (3-blockers,(i.e. as illustrated by pronethalol and sotalol, MJ1999) have been extensively reviewed (8,2.) One general point which needs to be emphasised is that the structure/activity pattern with respect to modifications of the ethanolamine side-chain closely parallels that found for the 3-stimulants, particularly with respect to type of amino-substituent required. Another point is that both blocking and stimulant activity lie with the R-enantiomer. 

The structure-activity relationships of glucocorticoids are based on two natural hormones, cortisol (3.8) and corticosterone (5.61). The characteristic structural features of these hormones are the conjugated 3-ketone, the 11-OH group, and the up-ketol side chain. Molecular modifications have been aimed at deriving compounds with glucocorticoid... 

Many other chemical modifications have been made to this remarkable series of compounds in the exploration of structure-activity relationships/473) Tertiary alcohols of general structure 214 (R = Me) have been dehydrated(348) by 98-100% formic acid to alkenes (217) via a C-19 carbocation intermediate. The anticipated carbocation rearrangement byproducts were also isolated. Dehydration was directed invariably to the side chain rather than to C-7, and the resultant alkenes were much reduced in analgesic potency. Carbocation rearrangements were catalyzed by concentrated HC1, and various bridged products have been investigated/349 350)... 

The discovery, in the early 1990s, that zanamivir was a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis of Neu5Ac2en based analogues of zanamivir. Much of this effort was a consequence of the fact that zanamivir (12) must be administered as a nasal spray, due to its poor oral bioavailability and rapid excretion [101,102], and the desire to identify new sialidase inhibitors with modified physicochemical properties. Several researchers have described structure-activity relationship studies based on zanamivir (vide infra), with most modifications reported at C-4, C-5, and the glycerol side-chain. 

In 1973, Koppel and his colleagues prepared a series of 7a-methoxy-cephalosporins to obtain some idea of structure-activity relationships within the series. The results (Table IX) show a wide variation in activity with modification of the 7 3-side-chain amide, as well as with changes in the group at C-3. In all cases, large differences are seen with the (3-lactamase-producing Serratia marcescens strain against which the non-methoxylated compounds are relatively inactive. 

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