Conformationally-restricted analogs

There are some problems involved in the use of conformationally restricted analogs. For example, some enzymes appear to be so highly specific... 

Besides this problem of designing conformationally restricted analogs for highly specific enzymes, there are Other problems to be considered in dealing with less specific enzymes. These are discussed later in the section on locked a-chymotrypsin substrates. 

Five conformationally restricted analogs of creatine now have been prepared. These are D-N-amidinoproUne, 19 LN-amidinoproline, 20 l-carboxymethyl-2-iminoimidazolidine, 21 l-carboxymethyl-2-iminohexa-hydropyrimidine, 22 and D,L3-methyl-4-carboxy-2-iminoimidazolidine (the L enantiomer is depicted in structure 23). 

Conformationally restricted analogs of substrates can be useful in elucidating both the substrate specificities and the product specificities of enzymes. The restriction can help stabilize an intermediate in the enzymatic process so that it may be isolated. Two or more otherwise structurally equivalent portions of a substrate may be rendered nonequivalent by the restriction so that potential differentiation of these portions by the enzyme in determining product specificity may be investigated. 

However, an almost classical attempt to generate an a, -unsaturated e-capro-lactam 87 involved a Knoevenagel condensation of 86 as the ring forming step. The material was employed in a synthesis of conformationally restricted analogs of some anti cancer agents (tetrahydrofolate analog) (Scheme 17) [24]. 

Teleocidines are known as tumor-promoting compounds characterized by an indolactam V core structure. Such indolactams adopt two stable conformations at room temperature. With the intention to investigate the biologically active conformer, Irie and Wender synthesized conformationally restricted analogs of indolactam V 50 (R=Me) [17]. Starting from desmethylindolactam... 

Some conformational studies of piperazic acids (hexahydropyridazine-3-carboxylic acids) have been reported <1998CSR437>. Piperazic acids are important compounds as they appear as subunit in many natural products (see Sections 8.01.6 and 8.01.12.2). They can be considered as rigid proline equivalents <1998JA80>. The conformation of derivatives of 3,4-dihydrophthalazine-2(l//)-carboxylic acid, a new conformationally restricted analog of phenylalanine, was also studied <1998T165>. 

In addition, conformationally-restricted analogs have been synthesized for two of the families and found to retain significant activity, providing evidence for the presence of turn conformations. 

Conformationally restricted analogs of (191)and (195a-i) have been described (231). 

These structural modifications resulted in decreased affinity for rat cerebral cortex tissue mid in most cases abolished efficacy at both centra and peripheral muscarinic receptors. Other conformationally restricted analogs of... 

Hashimoto, K., Oh tunc, Y., and Shirahama, H., Synthesis of conformationally restricted analogs of kainic acid. Is the conformation of the C4-substituent of kainoid important to its neiirocxcilalory activity TetrahedronIM, 36, 6235, 1995. 

Mussinu and co-workers (2003) recently reported a new series of rigid 1-aryl-l,4-dihydroindeno[l,2-c]pyrazole-3-carboxamides that are conformationally restricted analogs of SR141716A. These investigators found that conformational restriction resulted in markedly improved CB2 affinity and selectivity. These compounds were not screened for agonism/antagonism. 

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