Current Medicinal Chemistry - Volume 7, Issue 4, 2000

Different chemical structures have been found to possess different anti-inflammatory activities. Inflammation is a normal and essential response to any noxious stimulus which threatens the host and may vary from a localized response to a more generalized one. In view of the complexity and multitude of biochemical factors involved in inflammatory events, few general correlations of chemical structures and physicochemical properties with biological activities would be expected. Nevertheless some general features seem to be commonly associated with a large number of active drugs. However, these main features are not sufficient, but they could reflect certain physicochemical requirements for in vivo efficacy.QSAR is a useful means for maximizing the potency of a new lead compound. In the lead optimization phase of the synthetic project various QSAR procedures with the aid of computer-technology have been proposed. Among them, the classical Hansch approach has been widely used leading to quite a few successful examples. In the QSAR approaches, the prescription to optimise the lead structure is inferred from mathematical equations correlating variations in the potency of a certain biological activity with physicochemical and structural descriptors among congeneric molecules. The QSAR procedures are based on physical organic concepts and involve calculational operations. In the last years, quantum-chemical descriptors have been used in QSAR studies, because of the large physical information content encoded in many of the descriptors.Several anti-inflammatory receptor site models have been proposed. Since inflammation is a complex phenomenon involving interrelationships between humoral and cellular reactions through a number of inflammatory mediators, there is not much evidence on QSAR studies. Several QSAR studies have been reported obtaining only partial results. It was found that substituents which contribute to the high lipophilicity, were favourable to the activity. Substituents of short length (H, CH 3 ) have also a favourable effect. Satisfactory relationships between the in vivo activities and deprotonation energies, the HOMO energies and lipophilicities were found.

Theoretical calculations reveal that oligosaccharides are second to no other class of biochemical oligomery in terms of coding capacity. As integral part of cellular glycoconjugates they can serve as recognitive units for receptors (lectins). Having first been detected in plants, lectins are present ubiquitously. Remarkably for this field, they serve as bacterial and viral adhesins. Following a description of these branches of lectinology to illustrate history, current status and potential for medicinal chemistry, we document that lectins are involved in a wide variety of biochemical processes including intra- and intercellular glycoconjugate trafficking, initiation of signal transduction affecting e. g. growth regulation and cell adhesion in animals. It is thus justified to compare crucial carbohydrate epitopes with the postal code ensuring correct mail routing and delivery. In view of the functional relevance of lectins the design of high-affinity reagents to occupy their carbohydrate recognition domains offers the perspective for an attractive source of new drugs. Their applications can be supposed to encompass the use as cell-type-selective determinant for targeted drug delivery and as blocking devices in anti-adhe-sion therapy during infections and inflammatory disease. To master the task of devising custom-made glycans/glycomimetics for this purpose, the individual enthalpic and entropic contributions in the molecular rendezvous between the sugar receptor under scrutiny and its ligand in the presence of solvent molecules undergoing positional rearrangements need to be understood and rationally exploited. As remunerative means to this end, cleverly orchestrated deployment of a panel of methods is essential. Concerning the carbohydrate ligand, its topological parameters and flexibility are assessed by the combination of computer-assisted molecular-mechanics and molecular-dynamics calculations and NMR-spectroscopic measurements. In the presence of the receptor, the latter technique will provide insights into conformational aspects of the bound ligand and into spatial vicinity of the ligand to distinct side chains of amino acids establishing the binding site in solution. Also in solution, the hydrogen-bonding pattern in the complex can be mapped with monodeoxy and monofluoro derivatives of the oligosaccharide. Together with X-ray crystallographic and microcalorimetric studies the limits of a feasible affinity enhancement can be systematically probed. With galactoside-binding lectins as instructive model, recent progress in this area of drug design will be documented, emphasizing the general applicability of the outlined interdisciplinary approach.

Enaminones, enamines of β-dicarbonyl compounds, have been know for many years. In our initial account (Current Med. Chem. 1994, 1, 159-175), we reported on the anticonvulsant activity of a series of enaminones, notably methyl 4-[(p-chlorophenyl)amino]-6-methyl- 2-oxo-cyclohex-3-en-1-oate, 9a (R=CH 3 , R 1 =4-Cl), which, in animal tests, compared favorably to phenytoin and carbamazepine. Since that time, further research in our laboratory and other laboratories have expanded the therapeutic potential of these compounds. In addition to new anticonvulsant derivatives, we have uncovered a novel brain transport mechanism for the enaminones and developed a preliminary regression model for further synthetic direction. These topics will each be presented and elaborated.

AbstractPeptidomimetic RGD (Arg-Gly-Asp) analogs, which bind to glycoprotein (GP) IIb/IIIa on the surface of activated platelets, have been shown to inhibit platelet aggregation. Consequently, such RGD analogs can be used for the treatment of unstable angina pectoris and myocardial infarction. However, the low oral bioavailability for this class of compounds has been hindering their clinical development. Although many factors affect the oral activity of a drug, the limited membrane permeability of RGD analogs due to charge and high polarity is thought to be a major factor leading to the low oral activity of such compounds. Another factor is the metabolic lability of some such RGD analogs in the presence of proteases and peptidases. During the last 5 years, major progress has been made in the development of orally active RGD analogs. To improve the metabolic stability of RGD analogs, N-alkylation and C-terminal modification methods have been used successfully. To improve the membrane permeability of RGD analogs, two major strategies have been used. The first one is the strategy of prodrug. Along this line, simple ester prodrugs, double prodrugs, triple prodrugs, and cyclic prodrugs have been prepared with improved membrane permeability and oral activity. The second approach used is the de novo design of centrally constrained RGD analogs with improved oral bioavailability while maintaining the desired potency against GP IIb/IIIa. The lessons learned from the modification of RGD analogs could also help the future design of other peptidomimetic drugs with improved oral bioavailability.

Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication. Two main sites have been identified as poten-tial targets for the inhibition of HIV-1 PR, the active site and the interface, the latter being largely responsible for the stabilization of the enzyme dimeric structure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analogues and result from modifications of the peptidic scaffold into peptidomimetics. In order to improve their bioavailability, systematic biological screening and de novo design have been used to suggest new non-peptide inhibitors combining both antiviral potency and favorable pharmacokinetic properties. In parallel, compounds targeting other potential sites of inhibition have been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutations, have been shown to lead to HIV-1 PR inactivation. Cupric ion was described to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.

Gossypol, a disesquiterpene from cottonseed, exhibits multiple biological properties, including male antifertility activity and anticancer activity. Gossypol also inhibits the growth of numerous parasitic organisms and shows antiviral activity against a number of enveloped viruses, including the AIDS virus. Derivatives of gossypol, in which the aldehyde functional groups that contribute to toxicity have been modified, retain or even show enhanced biological activity. Ring substituted 2,3-dihydroxy- 1-naphthoic acids, which are structural analogs of gossypol, share with gossypol the ability to complex with dehydrogenases at the dinucleotide fold (Rossmann fold) with selectivity, suggesting that gossypol may be considered the prototype of a new class of drugs targeted to dehydrogenases. Most of the biological activities of gossypol and related compounds may result from inhibition of dehydrogenases.