Nonsteroidal antiinflammatory agents

Since the synthesis of aspirin in 1897, aspirin-like or nonsteroidal antiinflammatory drugs (NSAIDs) have been the mainstay of therapy for rheumatoid arthritis. Although of diverse chemical structure, these drugs not only exhibit the same antipyretic, analgesic and antiinflammatory therapeutic actions, but they also manifest identical toxic actions on the gastric mucosa and the kidney. This indicated that a single pharmacological effect was responsible for the properties of NSAIDs, a theory that was confirmed by the epochal discovery by Vane in 1971, that inhibition of the enzyme-producing prostanoids (cyclooxygenase [COX]) produced both the therapeutic and side effects of aspirin-like drugs. However, at equivalent antiinflammatory doses, different NSAIDs exhibited different degrees of toxicity. The reason for this was resolved by the discovery that prostaglandins at sites of tissue damage were synthesized by an inducible COX (COX-2) formed by a gene distinct from that producing the constitutive enzyme (COX-1), responsible for the formation of prostaglandins that serve an essential physiological function. Modification of the structure of drugs showing a moderately selective effect on COX-2, and the elucidation of the crystal structure of both enzymes, has paved the way for the synthesis of NSAIDs that are highly selective for the inducible enzyme and which are, therefore, antiinflammatory without the typical side effects of the classical NSAIDs. The focus on COX-2 has also expanded our knowledge of the pathophysiological significance of prostanoids and raised the possibility of new uses for selective COX-2 inhibitors, for example, in colon cancer, premature labor and possibly Alzheimer's disease. However, the clinical effects of chronic administration of potent, selective COX-2 inhibitors must await the results of ongoing clinical trials.     

Bis basic substituted diaminobenzobisthiazoles as potential antiarthritic agents.

A series of benzobisthiazoles were screened for antiinflammatory activity in the carrageenan paw edema and adjuvant arthritis tests. Compound 26, 2,6-bis(N,N-diethylamino)benzo[1,2-d:5,4-d']bisthiazole, was found to inhibit the swelling of the uninjected paw in the prophylactic adjuvant arthritis model with an ED50 of 2.3 mg/kg orally. As with most compounds of this series, 26 was inactive in acute model of inflammation, such as paw edema; like steroids, it showed activity in the granuloma pouch assay but did not inhibit cyclooxygenase, indicating a mode of action different from the classical nonsteroidal antiinflammatory drugs (NSAID's). At doses higher than those producing antiinflammatory activity, 26 had some immunoregulating properties.     

Novel targets for antibiotics

The rapid and extensive emergence of antibiotic resistant bacteria has resulted in a clear cut need to discover new antibiotics. Because of the many years of extensive screening, it is likely that most of the easy discoveries have been made and, therefore, new targets for antibiotics and new screening strategies for their discovery need to be developed. The approaches described in this overview are divided into several categories that are associated with different probabilities for a successful discovery. Approaches that are more likely to be successful include a continuation of classical discovery tactics including the chemical modification of extant structures, the use of new screens for classical targets (for example, the use of the enzyme DNA gyrase to discover new 4-fluoroquinolones), and the development of novel methods of drug delivery. These approaches, however, are likely to yield small incremental advances. More novel approaches should yield radically new chemical structures, however, the likelihood for a successful discovery will be lower than the classical approaches. The novel approaches include rational drug design, the discovery of new essential targets for antibiotics and using them for the purpose of drug screening, and the intervention in pathways necessary for pathogenesis. A middle of the road approach is to discover new agents that interfere with mechanisms of antibiotic resistance. Implicit in this overview is the need to develop new methods that result in real technologic advances. This may require a complete re-thinking of how antibiotics are discovered including the restricted use of live microbe killing assays as a primary screening tool.     

N-substituted urethanes as potential antiinflammatory agents

Sixteen N-substituted urethanes were investigated as potential antiinflammatory agents. Most of them showed no stronger activity than phenylbutazone. The most active in the xylene hyperemia test were N,N'-dicarbethoxy-N,N'-dicyclohexyl-1,3-diaminopropane (XVI) and cyclohexyl piperidine-1-carboxylate (XIII). None of the studied compounds showed analgesic activity.     

Carboxyarylindoles as nonsteroidal antiinflammatory agents.

An extensive series of carboxyarylindoles has been evaluated for antiinflammatory activity in the carrageenin paw edema assay. The requirements for optimal antiinflammatory activity in this series are relatively specific: a central pyrrole nucleus with (a) a 3-carboxy-4-hydroxyphenyl moiety substituted directly on the nitrogen, (b) a 2-phenyl group (R2) with a substituent of low electronegativity, (c) absence of a substituent in the 3 position (R3), and (d) a system fused across the 4,5 positions (X), which is lipophilic, quasiplanar, and does not interact sterically with the N-phenyl group. One derivative, 3-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5-dihydro-3H-benz[e]indole (42), has been selected for further study.     

Novel targets for antibiotics--an update

The emergence of widespread antibiotic resistance as an impediment in the treatment of bacterial diseases is of growing concern. In some instances, clinicians are left with few or no antibiotics for treatment of infections and this problem will more than likely grow in magnitude. One approach to get around the problem of antibiotic resistance is to develop new drugs with novel targets and mechanisms of action. Due to the 'newness' of these novel targets as therapeutic targets, the likelihood that resistance will initially be widespread is low. Three approaches are discussed in this overview: discovery of new essential genes that are expressed exclusively in vivo development of compounds that act on global bacterial gene regulators; and interference with virulence determinants. By exploiting virulence related attributes or genes expressed exclusively in vivo, the risk of resistance is reduced since inhibiting these products will probably alter the ecology (habitats) of these organisms rather than causing direct cell death. This might also lead to a selective targeting of pathogens with the beneficial consequence of ignoring organisms growing in their normal habitat, such as in the gastrointestinal tract or skin.     

Novel targets for platelet inhibition

Atherothrombosis often underlies coronary artery disease, stroke, and peripheral arterial disease. Antiplatelet drugs have come to the forefront of prophylactic treatment of atherothrombotic disease. Dual antiplatelet therapy of aspirin plus clopidogrel-the current standard-has benefits, but it also has limitations with regard to pharmacologic properties and adverse effects with often severe bleeding complications. For these reasons, within the last decade or so, the investigation of novel antiplatelet targets has prospered. Target identification can be the result of large-scale genomic or proteomic studies, functional genomics in animal models, the genetic analysis of patients with inherited bleeding disorders, or a combination of these techniques.     

Novel targets for malaria therapy

Malaria has emerged as one of the most debilitating parasitic infection with about 500 million cases reported annually and one million deaths worldwide. Currently, Plasmodium falciparum has developed resistance to almost all classes of antimalarials, thus precluding the use of those agents which once formed the cornerstone of malaria therapy. In lieu of this phenomenon, and taking into consideration the absence of an effective vaccine for malaria, the only way to combat the deadly parasite is to enrich the antimalarial cache with new molecules acting on fresh targets in the parasite. After potential targets have been validated, these targets can be used as basis for screening compounds to identify new leads followed by lead optimization. This review discusses novel targets of the malaria parasite that can be utilized to treat the disease.     

New targets for putative neuroprotective agents

A better understanding of intracellular pathways engaged in the neuronal cell death afforded us new targets for developing putative neuroprotectants. Also pharmacological or genomic intervention aimed to modulate the expression of endogenous neuroprotective or toxic agents is a very promising strategy. Taking into account enormous complexity of biochemical cascades involved in neurodegenerative processes, multipotential or combined pharmacological approaches seem to be more efficient in combating degenerative brain diseases. Moreover, an improved cell transplantation also adds to a plethora of methods, which are used to afford neuroprotection and promote neurorestoration. All those strategies are reviewed in the presented article.     

Novel therapeutic targets for autism

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules.     

Novel targets for HIV therapy

There are currently 25 drugs belonging to 6 different inhibitor classes approved for the treatment of human immunodeficiency virus (HIV) infection. However, new anti-HIV agents are still needed to confront the emergence of drug resistance and various adverse effects associated with long-term use of antiretroviral therapy. The 21st International Conference on Antiviral Research, held in April 2008 in Montreal, Canada, therefore featured a special session focused on novel targets for HIV therapy. The session included presentations by world-renowned experts in HIV virology and covered a diverse array of potential targets for the development of new classes of HIV therapies. This review contains concise summaries of discussed topics that included Vif-APOBEC3G, LEDGF/p75, TRIM 5α, virus assembly and maturation, and Vpu. The described viral and host factors represent some of the most noted examples of recent scientific breakthroughs that are opening unexplored avenues to novel anti-HIV target discovery and validation, and should feed the antiretroviral drug development pipeline in the near future.     

Novel targets for HIV therapy

There are currently 25 drugs belonging to 6 different inhibitor classes approved for the treatment of human immunodeficiency virus (HIV) infection. However, new anti-HIV agents are still needed to confront the emergence of drug resistance and various adverse effects associated with long-term use of antiretroviral therapy. The 21st International Conference on Antiviral Research, held in April 2008 in Montreal, Canada, therefore featured a special session focused on novel targets for HIV therapy. The session included presentations by world-renowned experts in HIV virology and covered a diverse array of potential targets for the development of new classes of HIV therapies. This review contains concise summaries of discussed topics that included Vif-APOBEC3G, LEDGF/p75, TRIM 5α, virus assembly and maturation, and Vpu. The described viral and host factors represent some of the most noted examples of recent scientific breakthroughs that are opening unexplored avenues to novel anti-HIV target discovery and validation, and should feed the antiretroviral drug development pipeline in the near future.     

Inhibition by various antiarthritic agents of murine splenic B cell colony formation

There is accumulated evidence suggesting that a polyclonal B cell activation is a primary etiologic defect of autoimmune diseases in both mice and humans. Based on this previous finding, the influence of various antiarthritic agents on lipopolysaccharide-induced B cell colony formation in mouse spleen cells was studied. When added to cell culture, aurothioglucose, chloroquine, and prostaglandin E1 had a suppressive effect on B cell colony formation at clinically relevant concentrations. A 50% suppression was obtained at 10(-7) to 10(-8) M for aurothioglucose, 10(-7) M for chloroquine, and 10(-7) to 10(-8) M for prostaglandin E1, respectively. All of the immunosuppressive drugs and glucocorticoids examined decreased the number of colonies with a variety of intensity. Nonsteroidal antiinflammatory drugs have only a slight inhibitory effect at high concentrations. Both penicillamine and levamisole had no effect on B cell colony formation. This experimental system might be useful in searching for new and unique drugs and in evaluating the mode of action of drugs used against autoimmune diseases.     

Pharmaceutical chemistry of minor analgesics and non-steroidal antiinflammatory agents

The paper represents the last (6th) part of a series about agents acting on the central nervous system. This time the minor analgesics and the non-steroidal antiinflammatory agents are surveyed. As previously, the material is divided into chapters of history, preparation; structure-properties-activity; therapeutical use; analysis.