Homochiral Drugs: A Demanding Tendency of the Pharmaceutical Industry

Abstract

The issue of drug chirality is now a major theme in the design and development of new drugs, underpinned by a new understanding of the role of molecular recognition in many pharmacologically relevant events. In general, three methods are utilized for the production of a chiral drug: the chiral pool, separation of racemates, and asymmetric synthesis. Although the use of chiral drugs predates modern medicine, only since the 1980's has there been a significant increase in the development of chiral pharmaceutical drugs. An important commercial reason is that as patents on racemic drugs expire, pharmaceutical companies have the opportunity to extend patent coverage through development of the chiral switch enantiomers with desired bioactivity. Stimulated by the new policy statements issued by the regulatory agencies, the pharmaceutical industry has systematically begun to develop chiral drugs in enantiometrically enriched pure forms. This new trend has caused a tremendous change in the industrial small- and large-scale production to enantiomerically pure drugs, leading to the revisiting and updating of old technologies, and to the development of new methodologies of their large-scale preparation (as the use of stereoselective syntheses and biocatalyzed reactions). The final decision whether a given chiral drug will be marketed in an enantiomerically pure form, or as a racemic mixture of both enantiomers, will be made weighing all the medical, financial and social proficiencies of one or other form. The kinetic, pharmacological and toxicological properties of individual enantiomers need to be characterized, independently of a final decision.

Resolute italian study in all comers

“…Two similarities are observed in these four binding cases: all the carboxyl groups are docked toward the Arg triad (Arg118, Arg292, and Arg371), accompanying with H‐bonding or/and electrostatic effects; the propenyl groups fit with the hydrophobic pocket close to residues Glu119 and Asp151. It is due to the high conservation of various NA active sites [59] and agrees with X‐ray experiments and previous MD simulations [15, 55]; nonetheless, each NA protein can effectively identify one BL stereoisomer [24, 60].…”

“…As shown in Scheme , five chiral‐C centers exist in BL, which will give rise to various stereoisomers. Understanding of drug chirality represents a grand challenge to us [20–25]. The different stereoisomers of drugs may exhibit distinct bioactivities.…”

Stereoselective Regulations of P-Glycoprotein by Ginsenoside Rh2 Epimers and the Potential Mechanisms From the View of Pharmacokinetics

“…Especially, since the thalidomide tragedy in 1960s [21], people have realized that the racemic mixtures and individual stereoisomers could exhibit totally different physiochemical and biochemical properties including carcinogenicity and teratogenicity [22]. Developing homochiral drugs has become a demanding tendency of the pharmaceutical industry [23].…”

Chiral Pharmaceuticals in Diverse Environmental Matrices: Occurrence, Removal and Toxicity

“…29,30 Os FQ com diferentes propriedades farmacocinéticas e farmacodinâmicas têm diferentes constantes de dissociação do local de ligação. Isso leva à resposta biológica diferente, 31 [31][32][33][34][35][36][37] As vantagens de formulações enantiomericamente puras são menor dose terapêutica, maior margem de segurança, menor variabilidade interindividual, menos interações medicamentosas e efeitos secundários. Ultimamente, temos assistido à avaliação de licenças para colocar no mercado fármacos enantiomericamente puros, administrados anteriormente como racematos (um processo chamado de chiral switching), assim como ao investimento em técnicas inovadoras de obtenção e controle de enantiômeros no desenvolvimento de novos fármacos.…”