Current Topics in Medicinal Chemistry - Volume 11, Issue 7, 2011

Although in 1986 E.J. Ariens wrote “Stereochemistry: a source of problems in medicinal chemistry”, chirality dominates in nature, in biological systems (i.e. aminoacids, receptors, enzymes) and in disposition and metabolic processes in which receptors and enzymes are involved. The complexity of biological systems, together with the different pharmacological and pharmacokinetic properties of enantiomers prompt m Read More

Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, Read More

Due to the advancement in chiral synthesis and separation technology and the new regulatory policies for chiral pharmaceuticals several manufacturers are replacing the previously marketed racemate chemicals with single enantiomeric products, the so called chiral switch. Though 25% of agrochemicals are chiral in nature, most of them are sold as racemates or enantiomer enriched products. Chiral pesticides and Read More

As the molecular etiology of cancer unravels, revealing the heterogeneous nature of the malignancy, multitarget drug treatments are more frequently advocated. Such therapeutic avenues often target kinases, the basic signal transducers in the cell. Because kinases share common evolutionary backgrounds, they also share many structural attributes, making it difficult for molecular targeted therapy to distinguish be Read More

Small molecule kinase inhibitors are important tools for studying cellular signaling pathways, phenotypes and are, occasionally, useful clinical agents. With stereochemistry pervasive throughout the molecules of life it is no surprise that a single stereocenter can bestow a ligand with distinct binding affinities to various protein targets. While the majority of small molecule kinase inhibitors reported to date are achiral, a number Read More

Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokine Read More

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review provides an overview of most papers reporting the influence of stereochemistry on PPAR activation. Some cases in w Read More

The seco-steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is the most potent natural metabolite of vitamin D3 and regulates primarily calcium and phosphate homeostasis, but also as a regulator of specific differentiation and of the immune system. Most, if not all, of the biological actions of 1α,25(OH)2D3 are mediated through its specific receptor, the vitamin D receptor (VDR), which is a member of the nuclear rec Read More

The (18 kDa) Translocator Protein (TSPO) was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named “Peripheral-type benzodiazepine receptor (PBR)”. It is an evolutionarily wellconserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleo Read More

The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally α-amino acids with one or more stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there ar Read More