Isomers
Kate McCombe, Lara Wijayasiri, Paul Hatton, David Bogod in The Primary FRCA Structured Oral Examination Study Guide 2, 2017
Interestingly, thalidomide is an enantiomer; one form gives the desired antiemetic effect, but the other is responsible for the teratogenic side effects. While the drug companies in the 1970s realised this, they did not appreciate that a proportion of the safe enantiomer is converted to the toxic form in vivo, and so marketed it with catastrophic effect. Thalidomide is being used again as a chemotherapy agent. Diastereoisomers:They possess more than one chiral centre and so they cannot form mirror images of each other.Examples include atracurium, which has four chiral centres.
Principles
Sarah Armstrong, Barry Clifton, Lionel Davis in Primary FRCA in a Box, 2019
Optical isomers (enantiomers) are compounds that are mirror images of each other around a central atom (chiral centre) Originally classified according to their ability to rotate the plane of polarized light in opposite directions (levo/dextro isomers)This classification has been superseded by the R (rectus)/S (sinister) system, which describes the configuration of the atoms around the chiral atom according to the molecular weights of the other atomsA racemic mixture contains equal amounts of the two isomers and consequently has no optical activityDiastereoisomers have more than one chiral centre and are not mirror images of each other
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Debarshi Kar Mahapatra, Sanjay Kumar Bharti in Medicinal Chemistry with Pharmaceutical Product Development, 2019
Argatroban (Figure 7.9) is a small (527 Da) synthetic piperidine carboxylic acid derivative of L-arginine. It is a univalent DTI that non-covalently and reversibly binds to the active site on thrombin as shown in Figure 7.7. Commercially available argatroban is a racemic mixture of the R- and S-diastereoisomers in a ratio of approximately 65 to 35, with the S-isomer having about twice the thrombin-inhibitory potency of the R-isomer. It is licensed in the United States for the prophylaxis or treatment of thrombosis in patients with HIT and for anticoagulation in patients with a history of HIT or at risk of HIT undergoing PCI. It is given as an intravenous infusion and does not require a bolus injection [68, 69].
In vitro metabolism assessment of thiacloprid in rainbow trout and rat by LC-UV and high resolution-mass spectrometry
Published in Xenobiotica, 2021
Jose Serrano, Richard C. Kolanczyk, Brett R. Blackwell, Barbara R. Sheedy, Mark A. Tapper
The accurate mass for THI and metabolites TM1, TM2 and TM3, as determined from LC-HR-MS experiments (M + H), was 253.10226, 228.03574, 126.05475 and 128.02740 Da respectively, with all detected structures within a mass error <7 ppm (see Supplemental Tables S5 and S6). Specifically, LC-MS mass chromatograms of THI slice exposures showed the presence of two isomers for both TM1 and TM2 corresponding to the Z-/E-diastereoisomers of TMI (retention times of 1.189 and 1.437 min, respectively), and the enol-/aldehyde-tautomers of TM2 (0.917 and 1.233 min, respectively; Supplemental Table S6). Diastereoisomers are stereoisomers of the same constitution, but the molecules do not have a mirror-image relationship and have different physical and chemical properties. On the other hand, tautomers are molecules with the same molecular formula but different connectivity that are formed in common acid- or base-catalyzed processes.
Absorption, distribution, metabolism and excretion of darolutamide (a novel non-steroidal androgen receptor antagonist) in rats
Published in Xenobiotica, 2020
Päivi Taavitsainen, Hille Gieschen, Timo Korjamo, Marja Kähkönen, Chira Malmström, Olaf Prien, Michael Niehues, Steffen Sandmann, Wiebke Janssen, Mikko Koskinen
One interesting feature of darolutamide PK is the ability of the two diastereoisomers to interconvert metabolically. Both in vitro and in vivo results show that after dosing of one individual diastereoisomer, the other diastereoisomer also appears. This interconversion takes place through the keto-metabolite, as established by incubating keto-darolutamide in hepatocytes. Interconversion occurred rapidly in vivo in rats, the other diastereoisomer being detected within 15 min post-dosing. Similar diastereoisomer–plasma ratios were observed with single dose; and were maintained at high doses. Nevertheless, there was a tendency towards a slight preference for (S,S)-darolutamide after repeated dosing. This is against the observation that the intrinsic rate of metabolism is likely higher for (S,S)- than (S,R)-darolutamide in rats (Figure 6(A)). However, reduction of keto-darolutamide seems to favour the formation of (S,S)-darolutamide, resulting in increased exposure in vivo (Figure 6(B)). Quantitative mechanistic assessment of the interconversion deserves further study, as the current in vitro hepatocyte studies qualitatively support the in vivo results.
Comparative toxicity and toxicokinetic studies of oxiracetam and (S)-oxiracetam in dogs
Published in Xenobiotica, 2019
Tian-tian Liu, Xin-miao Guo, Zu-yuan Rong, Xiang-feng Ye, Jin-feng Wei, Ai-ping Wang, Hong-tao Jin
As a consequence of the rapid advances in chiral synthesis and separation technologies, combined with new regulatory policies for chiral pharmaceuticals, chiral drugs have become an important focus for research and development of new molecular entities (Calcaterra & D'Acquarica, 2018; Nunez et al., 2009; Srinivas, 2004). Stereoisomers (enantiomers and diastereoisomers) not only differ from one another in their pharmacological effects, but also in their pharmacokinetic (adsorption, distribution, biotransformation, and excretion) profiles (Brocks, 2006; Hutt, 2007) and toxicological properties (Natarajan & Basak, 2011; Smith, 2009). Understanding the stereospecificity of in vitro and in vivo pharmacokinetics/toxicokinetics may assist in delineating the developmental path of the racemate and/or the pure enantiomers. The differential actions and toxicities determine enantiomer selection to maximize clinical effects or mitigate drug toxicity. Toxicological evaluation of chiral drugs, therefore, deserves increased attention.
Related Knowledge Centers
- Enantiomer
- Epimer
- Galactose
- Stereochemistry
- Stereoisomerism
- Stereocenter
- Organic Reaction
- Stereoselectivity
- Cahn–Ingold–Prelog Priority Rules
- Fischer Projection