- Volume 1, Issue 1, 2004

Medicinal Chemistry has matured as a discipline, and there is no better time than the present to be a medicinal chemist. One of the primary driving forces in this renaissance is the increased value added by collaborations with biology, pharmacology, toxicology, spectroscopy, and allied fields earlier in the drug discovery process. The modern practicing medicinal chemist is inundated with new data, including in vitro and in vivo Read More

The dynamic and highly regulated processes of bone remodeling involve two major cells, osteoclasts and osteoblasts, both of which command a multitude of cellular signaling pathways involving protein kinases. Of the possible kinases in these cells, Src tyrosine kinase stands out as a promising therapeutic target for bone disease as validated by Src knockout mouse studies and in vitro cellular experiments, suggesting Read More

Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases suc Read More

The functions of zinc proteases have been implicated in a host of physiological and pathological processes in living organisms. Mechanism-based inhibitors are highly sought as biologically active molecules that afford high selectivity in targeting specific enzymes. Mechanism-based inhibitors for zinc dependent proteases have been developed in the past several years. These inhibitors exploit the chemistry inherent to transition m Read More

Non steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies for rheumatic diseases. But NSAIDs produce serious adverse effects, the most important being gastric injury up to gastric ulceration and renal damage. Several strategies have been adopted in order to avoid these shortcomings, expecially gastrointestinal toxicity. So, non steroidal anti-inflammatory drugs have been associated with ga Read More

Specific mutations in the ras gene impair the guanosine triphophatase (GTPase) activity of Ras proteins, which play a fundamental role in the signaling cascade, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not a Read More

The last five years has seen an explosion of research into inhibitors of Factor Xa as potential antithrombotic agents. Aventis Pharma through its founder company Rhone-Poulenc Rorer was a participant in this effort and contributed significantly to the discovery of new inhibitors in recent years. This chapter traces the systematic development of the former Rhone-Poulenc Rorer factor Xa program from conception to the re Read More

Diabetes Mellitus refers to a spectrum of syndromes characterized by abnormally high levels of glucose in blood. These syndromes are associated with an absolute (Type 1 diabetes) or relative (Type 2 diabetes) deficiency of insulin, coupled with varying degrees of peripheral resistance to the actions of insulin. Clinical studies have shown that controlling hyperglycemia significantly reduces the appearance and progression of th Read More

Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the world's population. The number of diabetics is increasing by 4-5% per year with an estimated 40-45% of individual's over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impair Read More

The enediynes remain among the most potent antitumoral agents to have been discovered in the past decade. Following prodrug activation, the enediynes undergo cycloaromatization reactions resulting in formation of highly reactive diradical intermediates. The diradical species engage in atomtransfer chemistry to produce neutral arene products, in the process inducing damage to key macromolecules. Several of the natu Read More

Combinatorial technology for the generation of molecular diversity has evolved as an integrated component in accelerated drug discovery process. During the emerging days of combinatorial chemistry, solidphase organic synthesis has been the leading strategy for the production of large libraries for lead discovery. As combinatorial techniques for the library synthesis has evolved, solution-phase synthesis of smaller, target Read More

The technology of nuclear magnetic resonance spectroscopy continues to advance at a rapid pace. The development of NMR based rapid high throughput screening methods to identify small organic molecules in complex mixtures that bind to specific protein targets has proven to be an effective method in lead identification. NMR coupled to liquid chromatography has opened a new door to the quantitative and qualitative Read More

Electrospray ionization (ESI) and matrix-assisted laser desorption / ionization (MALDI) mass spectrometric methods useful for exploratory and early discovery drug screening are reviewed. All methods described involve studies of non-covalent complexes between biopolymer receptors and small molecule ligands formed in the condensed phase. The complexes can be transferred directly into the gas phase by ESI-MS using gentle Read More

The phosphodiesterases (PDEs) are responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP, respectively). They are classified into 11 major families (PDE1-11) and the type 4 phosphodiesterase (PDE4) is a cAMP-specific enzyme localized in airway smooth muscle cells as well as in immune and inflammatory cells. The PDE4 activity is associated with a wide variety of diseases Read More

Selective Serotonin reuptake inhibitors (SSRIs) have contributed to the major advances in the treatment of depression and other psychiatric diseases. This review summarises current knowledge concerning the SSRI class of drugs and discusses the importance of secondary pharmacology in the mechanism of action and effectiveness of these drugs. This area of research has shed light on the pharmacological mechanisms Read More

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of β-amyloid peptide (Aβ) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but Read More

Oxidative stress in brain is emerging as a potential causal factor in aging and age-related neurodegenerative disorders. Brain tissue from living patients is difficult to acquire; hence, animal models of aging and age-related neurodegenerative disorders, though not perfect models, have provided tissue to study the role of oxidative stress in these disorders. In this review, the central role of oxidative damage in models of a Read More

Several lines of evidence indicate that G-protein coupled receptors (GPCR) may exist in a state that allows a tonic level of stimulation in vivo (constitutive activity). Several native forms of GPCR, when expressed in recombinant cell lines, display significant signal transduction stimulation in the absence of activating ligand. Many GPCR, including four serotonin receptors, display robust constitutive activation upon the mutation Read More

About 30% of drug candidate molecules are rejected due to pharmacokinetic-related failures. When poor pharmaceutical properties are discovered in development, the costs of bringing a potent but poorly absorbable molecule to a product stage by “formulation” can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stages of discovery. This review will co Read More