Current Pharmaceutical Design - Volume 9, Issue 15, 2003

Obesity is a heritable disease that affects millions of people, is disproportionately prevalent in some ethnic groups, and has serious health consequences. Molecular mechanisms causing excessive adiposity are being discovered at an unprecedented rate in animal models. The same cannot be said for humans and, in fact, the etiology of obesity in the majority of people remains unknown. Furthermore, we are far from fully understanding how an obesogenic environment increases the severity of the disease in people who are genetically susceptible to weight gain. Due to these uncertainties, it is perhaps not surprising that current antiobesity treatments are moderately effective at best. This manuscript provides a brief review of current and future strategies for the treatment of obesity and how they relate to our current knowledge of its pathophysiology. It is concluded that there are reasons to be moderately optimistic that effective pharmacological means to palliate obesity will eventually be identified. However, reversing the current pandemic will require a greater understanding not only of the molecular and physiological underpinnings, but also social and political causes of this disease

Neuropeptide Y (NPY), the most abundant peptide present in the mammalian brain, exhibits a wide spectrum of central and peripheral activities mediated by at least six G-protein coupled receptors. The latter observation, and the implication of NPY in the pathophysiology of feeding, seizures, diabetes, intestinal dysfunction, cardiovascular diseases and respiratory disorders, have led to vigorous efforts to dissociate various effects of NPY and develop receptor selective ligands required for fundamental investigations, and possible clinical utility. These efforts have made significant advancement in the development of antagonists, especially for Y1 and Y5 receptors mediating NPY effects on feeding and / or thermogenesis. However, only a limited progress has been made in the case of Y2 ligands, and none in the case of Y4 ligands. Moreover, most of the nonpeptidic ligands developed to date have little use clinically because of their solubility and toxicity problems and their limited passage through blood-brain barrier. Furthermore, no progress has been made in developing lower molecular weight agonists, which may also have clinical potential in treating seizures, intestinal dysfunction, respiratory disorders, cachexia and anorexia. Thus, despite significant advances, NPY research is expected to attract scientists for years to come in the pursuit to develop clinically useful ligands. The recent advances in the peptide drug delivery techniques have given added impetus for these efforts. This article reviews the usefulness of widely used ligands as well as those developed more recently.

Diabetes is among the largest contributors to global mortality through its long term complications. The worldwide epidemic of type 2 diabetes has been stimulating the quest for new concepts and targets for the treatment of this incurable disease. A new target is glycogen phosphorylase (GP), the main regulatory enzyme in the liver responsible for the control of blood glucose levels. One of several approaches to influence the action of GP is the use of glucose derivatives as active site inhibitors. This field of research commenced 10-15 years ago and, due to joint efforts in computer aided molecular design, organic synthesis, protein crystallography, and biological assays, resulted in glucopyranosylidene-spiro-hydantoin 16 (Ki = 3-4 μM) as the most efficient glucose analog inhibitor of GP of that time. The present paper surveys the recent developments of this field achieved mainly in the last five years: the synthesis and evaluation of glucopyranosylidene-spiro-thiohydantoin 18 (Ki = 5 μM) which has proven equipotent with 16, and is available in gram amounts; furanosylidene- and xylopyranosylidene-spiro-(thio)hydantoins whose ineffectiveness (Ki > 10 μM) confirmed the high specificity of the catalytic site of GP towards the D-glucopyranosyl unit;“open” hydantoins like methyl N-(1-carboxamido-D-glucopyranosyl)carbamate 37 (Ki = 16 >M) and N-acyl-N'-(β-Dglucopyranosyl) ureas among them the to date best glucose analog inhibitor N-(2-naphthoyl)-N'-(β-D-glucopyranosyl)urea (35, Ki = 0.4 μM) which can also bind to the so-called new allosteric site of GP; C-(β-D-glucopyranosyl)heterocycles (tetrazole, 1,3,4-oxadiazoles, benzimidazole (Ki = 11 μM), and benzothiazole). Iminosugars like isofagomine (45, IC50 = 0.7 μM), noeuromycin (53, IC50 = 4 μM), and azafagomine (54, IC50 = 13.5 μM) also bind strongly to the active site of GP, however, substitution on the nitrogens makes the binding weaker. The natural product five-membered iminosugar DAB (56) exhibited IC50 ∼ 0.4-0.5 μM. Azoloperhydropyridines which can be regarded iminosugar-annelated heterocycles show moderate inhibition of GP: nojiritetrazole 12 (Ki = 53 μM) is the best inhibitor and fewer nitrogens in the five-membered ring weakens the binding. Physiological investigations have been carried out with N-acetyl-β-Dglucopyranosylamine 6, spiro-thiohydantoin 18, isofagomine 45, and DAB 56 to underline the potential use of these compounds in the treatment of type 2 diabetes. Computational methods suggest to synthesize further anomerically bifunctional glucose derivatives which may be good inhibitors of GP.

While the biological reaction of chymase have been often studied for ten years, the pathophysiological role of chymase has not been fully elucidate due to a lack of effective inhibitors featuring potent inhibitory activity, specificity, and metabolic stability. Recently the discovery of a structurally varied range of novel nonpeptidic inhibitors presents new opportunities to explore the role of chymase under both physiological and pathophysiological conditions and to develop therapeutic agents for chymase-induced diseases. In this article the structure and the inhibitory mechanism of nonpeptidic chymase inhibitors are discussed, with special emphasis on design and structure-activity relationships of pyrimidinone derivative where inhibitory activity, protease selectivity, and pharmacokinetic profile are clarified.

The selective accumulation and activation of leukocytes in inflamed tissues contributes to the pathogenesis of inflammatory and autoimmune diseases such as infection, rheumatoid arthritis, allergic asthma, atopic dermatitis, and multiple sclerosis. A substantial body of reports suggests that chemokines and their receptors, which belong to a family of seven transmembrane G-protein coupled receptors (GPCR), may be involved in the selective accumulation and activation of leukocytes in inflamed tissues, and in the pathogenesis of inflammatory and autoimmune diseases. One such receptor is CCR1 which is a receptor for CC chemokines, such as CCL5 (RANTES) and CCL3 (MIP-1α). The involvement of CCR1 in immunological diseases now is documented in several preclinical studies with CCR1 deficient mice, anti-CCR1 antibodies and CCR1 antagonists, suggesting that CCR1 may be an attractive therapeutic target for a variety of diseases. Publications and patents describing CCR1 antagonists and their pharmacological effects have recently been disclosed. This review highlights the biology and pathophysiology of CCR1, and some of its currently reported antagonists. Additionally, our approach to CCR1 drug discovery is summarized.

Peptides and proteins are essential to many biological processes. The interaction between the peptide ligands and their receptor targets commonly involves β-turn structures. Yet poor bioavailability and unfavorable pharmacokinetics significantly compromise the use of peptides as drugs. Thus, there has been a great deal of interest in the design of peptidomimetics (modified peptides) as therapeutic agents by mimicking β-turn structures. This review highlights the importance of β-turn in the design of various peptidomimetics for many diseases. This review also outlines several β-turn mimicking strategies and its application in the design of potent peptide analogues. β-turn mimetics often tend to be more rigid in positioning the critically important amino acid residues and thus optimize the surface conformation for productive interaction with the receptors.