Conformational restriction rigid compounds

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>. 

The development of rigid histamine analogues is important for the determination of the H3 receptor pharmacophore as the conformations of these compounds only allow restricted spatial orientation of the imidazole ring with respect to the basic nitrogen in the side... 

I) a chiral compound, containing heteroatoms, which interacts with organometallic compound(s) generating structurally rigid chelate complexes as intermediates, caul (II) such intermediates should necessarily be of conformationally restricted cis-fused 5-membered ring structure. 

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. 

Unfortunately, this set of altogether 20 compounds does not contain any rigid molecules, but some of them are, at least in parts, conformationally restricted. This is true, for example, for clothiapine and irindalone as well as spiperone, while the members of the ketanserin subfamily, which contain five major rotatable bonds, show a high degree of conformational freedom. 

Figure 3 Structural alignments with discrete properties. Methods are based on discrete properties using the DG algorithm (1) or clique-detection (11) as implemented in distance comparisons (DISCO), and Apex-3D. The structure representation, based on discrete properties, resorts to one atomic descriptor (I), usually the atom type, or multiple atomic or site descriptors (II). In the first method (I), the conformational analysis is restricted to the generation of molecular geometries which allow a common arrangement of selected phaimacophoric moieties present in a rigid compound used as template. In the second method (II), the conformational analysis procedure may involve a systematic enumeration of all the possible conformadons for each ligand. The search similarity is directed towards the confirmation of a predefined pharmacophore postulated by the modeler or from some classical SAR in the case of the active analog approach (1), or the automated identification of pharmacophores and bioacdve conformations (II)...

NMR parameters, such as chemical shifts and coupling constants, have been extensively investigated through the use of organic compounds that exhibit restricted rotation, such as oximes. NMR data are routinely used in determination of the stereochemistry of organic compounds and rigid strucmres, such as oxime conformers, can help in the interpretation of many of the physical and chemical properties that are associated with effects of lone pairs on different types of systems that contain nitrogen. 

The author mentions the work of Cannon who has carried out some of the best studies on the effects of rigidification of DA analogues. The latter compounds are certainly much better examples of this concept than compounds XII and XIII which are not really "rigid" but merely analogues with restricted conformational freedom. 

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