Lead compounds novel

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

The resulting compound libraries thus include many analogs of the lead compounds, which can be used in additional screens for novel leads. 

The development of new chemotherapeutic agents for a particular disease state continues to depend to a significant degree on the discovery of a lead compound , which can be further developed into a viable drug candidate. A very important aspect of this process is to find novel substances that will provide a new mode of action for the treatment of a specific disease. From a historical standpoint, the isolation of novel substances from natural sources has often provided this lead compound. The number of new drugs and their origin for the period 1981-2002 has recently been summarized [1], and, of 79... 

Several reports indicate the involvement of superoxide in the mediation of tolerance [67-69]. Based on these reports, a bifunctional superoxide dismutase-mimic NO donor was designed by Haj-Yehia s group [70]. The nitrate ester was incorporated into a nitroxide such as 3-hydroxymethyl-2,2,5,5-tetramethyl-l-pyrroHdinyloxy (HMP) by its conversion into 3-nitratomethyl-PROXYL (NMP) (Scheme 1.7). HMP is a stable, metal-independent, low-molecular weight SOD-mimic with excellent cell-permeability. So NMP is the first compound that can simultaneously generate NO and destroy superoxide. This may lead to novel nontolerance-inducing nitrovasodila-tors. 

Combinatorial approaches have been most successful when information about the target biomole cule has been considered in the design of the library. However, for many biomolecules, structural or mechanistic information is not available or does not provide sufficient insight to enable productive library design Also, lead compounds are not available for many targets, and in some cases, novel motifs for binding are desired. Under these circumstances, it is no surprise that the successful application of combinatorial chemistry has been less fre-... 

Bacterial resistance to conventional antibiotics has become a serious problem in infection control, and has led to intensive research efforts to develop an effective novel antimicrobial agent. Antimicrobial peptides have already played a crucial role in pharmaceutical research as biomedically useful agents or as lead compounds for drug development. More specifically, cyclic peptides have shown some potential as a possible new class of... 

Our interest in such compounds stems mainly from the possibility that they might be useful precursors to new classes of phosphorus-containing polymers or cyclic oligomers. Functional linkages such as E = NSiMe3 or CR SiMe3 could serve as sites for condensation-polymerization reactions, leading to novel cyclic or polymeric sys terns, ... 

The discovery of DHFR inhibitor NGD-157 demonstrates that ALIS is an efficient system for identifying novel, bioactive lead compounds from large combinatorial libraries. A single ALIS experiment containing over 2500 compounds is complete in under 10 min, allowing more than 250 000 compounds to... 

This relatively small DCL yielded the first peptidic ligand for G-quadruplex DNA, providing a lead compound for the further development of novel G-quadruplex ligands with possible therapeutic utility. 

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