Proposal for a New Stereochemically Informative Nonproprietary Drug Naming System.

Background: The stereochemical aspects of drugs are generally recognized as fundamentally important influencers of drug action and disposition. Nevertheless, the nonproprietary names of the vast majority of stereochemically relevant therapeutic agents in the USP Dictionary of United States Adopted Names (USAN) and International Drug Names and in the WHO Drug Information listings provide no information on the stereochemical aspects.

Objective: In view of the importance of stereochemistry in drug action and disposition, it is desirable to have a nonproprietary drug nomenclature system that provides basic information on the stereochemical identity and composition of drugs.

In defense of Louis Pasteur: Critique of Gerald Geison's deconstruction of Pasteur's discovery of molecular chirality.

Louis Pasteur discovered the phenomenon of molecular chirality, based on his studies of tartrate crystals. His finding remains one of the most important discoveries in the history of chemistry and a fundamentally important chemical phenomenon, with essential implications in biology. In his 1995 book The Private Science of Louis Pasteur, the eminent historian of science Gerald L.

Molecular chirality: language, history, and significance.

In this chapter some background material concerning molecular chirality and enantiomerism is presented. First some basic chemical-molecular aspects of chirality are reviewed, after which certain relevant terminology whose use in the literature has been problematic is discussed. Then an overview is provided of some of the early discoveries that laid the foundations of the science of molecular chirality in chemistry and biology, including the discovery of the phenomenon of molecular chirality by L.

Early history of the recognition of molecular biochirality.

This opening chapter recalls the history of the discoveries that led to the appreciation of the nature and importance of molecular chirality in biology, as well as the development of stereochemistry as an interdisciplinary field connecting chemistry and biology. The discoveries described cover roughly the period of ca. 1840-1940, although certain relevant events of earlier or later times are also addressed.

The discovery of stereoselectivity at biological receptors: Arnaldo Piutti and the taste of the asparagine enantiomers--history and analysis on the 125th anniversary.

In 1886, Italian chemist Arnaldo Piutti isolated, for the first time, d-asparagine, the enantiomer of the known l-asparagine. He obtained 100 g of D-asparagine from 6500 kg of vetches. Using an ingenious synthetic scheme, Piutti established the chemical structure of asparagine and demonstrated that his isolation of D-asparagine from plants was not the result of the racemization of L-asparagine during the extraction procedure.

Stereochemical vocabulary for structures that are chiral but not asymmetric: History, analysis, and proposal for a rational terminology.

Asymmetric objects are necessarily chiral, but a structure may be chiral and not asymmetric if it possesses one or more proper rotation axes. Chiral but not asymmetric molecules are important in chemistry and its applications, but no suitable term exists for the designation of such structures, and their terminology in the literature is confused and chaotic. Dissymmetric has been redefined by some authors as "chiral but not asymmetric," in conflict both with Pasteur's definition of the term as "not superposable on its mirror image" (without other restrictions, i.

Stereoselective determination of the epimer mixtures of itraconazole in human blood plasma using HPLC and fluorescence detection.

Itraconazole is an antifungal drug widely used in a variety of fungal infections, which have become a significant public-health problem in recent decades. Itraconazole is a chiral drug consisting of two diastereoisomeric racemates, i.e.

Louis Pasteur, language, and molecular chirality. I. Background and dissymmetry.

Louis Pasteur resolved sodium ammonium (±)-tartrate in 1848, thereby discovering molecular chirality. Although hindered by the primitive state of organic chemistry, he introduced new terminology and nomenclature for his new science of molecular and crystal chirality. He was well prepared for this task by his rigorous education and innate abilities, and his linguistic achievements eventually earned him membership in the supreme institution for the French language, the Académie française.

Computational discovery of novel low micromolar human pregnane X receptor antagonists.

Very few antagonists have been identified for the human pregnane X receptor (PXR). These molecules may be of use for modulating the effects of therapeutic drugs, which are potent agonists for this receptor (e.g.

When did Louis Pasteur present his memoir on the discovery of molecular chirality to the Académie des sciences? Analysis of a discrepancy.

Louis Pasteur presented his historic memoir on the discovery of molecular chirality to the Académie des sciences in Paris on May 22nd, 1848. The literature, however, nearly completely ignores this date, widely claiming instead May 15th, 1848, which first surfaced in 1922 in Pasteur's collected works edited by his grandson Louis Pasteur Vallery-Radot. On May 21st, 1848, i.

The discovery of biological enantioselectivity: Louis Pasteur and the fermentation of tartaric acid, 1857--a review and analysis 150 yr later.

Nearly a decade after discovering molecular chirality in 1848, Louis Pasteur changed research direction and began investigating fermentations. Conflicting explanations have been given for this switch to microbiology, but the evidence strongly suggests that Pasteur's appointment in 1854 to the University of Lille--an agricultural-industrial region where fermentation-based manufacturing was of great importance--and an appeal for help in 1856 by a local manufacturer experiencing problems in his beetroot-fermentation-based alcohol production played a significant role. Thus began, in late 1856, Pasteur's pioneering studies of lactic and alcoholic fermentations.

Carl Friedrich Naumann and the introduction of enantio terminology: a review and analysis on the 150th anniversary.

Enantiomorphism and enantiomorphous were the first enantio-based terms, introduced 150 years ago, by Carl Friedrich Naumann, a German crystallographer, to refer to non-superposable mirror-image crystals. The terminology was not adopted by Pasteur, the discoverer of molecular chirality, and was not embraced at first in the stereochemical context, until it was accepted in 1877 by Van't Hoff in the German edition of his proposal for the tetrahedral asymmetric carbon atom. In the 1890s the use of enantio terms began to spread in the research literature, and many new derivatives of Naumann's original two terms were subsequently introduced.

Determination of the absolute configuration and solution conformation of the antifungal agents ketoconazole, itraconazole, and miconazole with vibrational circular dichroism.

The absolute configuration assignments of three antifungal agents, (+)-(2R,4S)-ketoconazole, (+)-(2R,4S)-itraconazole (with (S)-configuration at the sec-butyl group) and (+)-(S)-miconazole nitrate have been confirmed by using vibrational circular dichroism (VCD). For these three antifungal drugs, this study also provides evidence for the most abundant conformations of miconazole and for the relative conformations of the azole, dichlorophenyl, and methoxyphenyl groups in ketoconazole and itraconazole, in chloroform solution.

New single-isomer compounds on the horizon.

In 1992, the Food and Drug Administration (FDA) issued new guidelines governing stereoisomerism in new-drug development. The guidelines strongly encourage the development of single isomers and discourage stereoisomeric (eg, racemic) mixtures. As a result, most new chiral drugs are being developed as single enantiomers (ie, single isomers).

Single-isomer science: the phenomenon and its terminology.

Single-isomer drugs are of great importance in modern therapeutics. In this article, the basics of the underlying phenomenon are explained. Some molecules are chiral, ie, their mirror image is not superposable on the original.

Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates.

Racemic ketoconazole (KTZ) was the first orally active azole antifungal agent used in clinical practice and has become widely used in the treatment of mucosal fungal infections associated with AIDS immunosuppression and cancer chemotherapy. However, the use of KTZ has been limited because of adverse drug-drug interactions. KTZ blocks ergosterol biosynthesis by inhibiting the fungal cytochrome P450 (CYP51).

Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19.

Methadone is a clinically used opioid agonist that is oxidatively metabolized by cytochrome P450 (CYP) isoforms to a stable metabolite, EDDP. Methadone is a chiral drug administered as the racemic mixture of (R)-(-)- and (S)-(+)-methadone, but (R)-methadone is the active isomer. The cytochrome P450 (CYP) isoform involved in methadone's metabolism is thought to be CYP3A4, but human drug-drug interaction studies are not consistent with this.