The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

Synopsis of some recent tactical application of bioisosteres in drug design.

Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet

Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3 H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

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Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences

The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compounds where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clinical candidates, and highlights both opportunities and challenges of this strategy.

Applications of Deuterium in Medicinal Chemistry

Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoiesis stimulating agents (ESAs) and red blood cell transfusions.

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Erythropoietin or darbepoetin for patients with cancer

Objective: To evaluate the therapeutic efficacy and safety of epoetin zeta, compared with epoetin alfa, in maintaining target haemoglobin (Hb) concentrations in patients with anaemia and chronic ki...

Comparison of the therapeutic effects of epoetin zeta to epoetin alfa in the maintenance phase of renal anaemia treatment

Objective: To assess the therapeutic equivalence of epoetin zeta and epoetin alfa for correction of haemoglobin (Hb) concentration in patients with anaemia and chronic kidney disease (CKD) stage 5 maintained on haemodialysis.Study design: In total, 609 patients with CKD and anaemia (Hb < 9 g/dL) were randomly assigned to receive either epoetin zeta or epoetin alfa intravenously, one to three times per week for 24 weeks. Dosing was titrated individually to achieve a stable, target Hb concentration of 11–12 g/dL. Primary endpoints were the mean weekly dose of epoetin per kilogram of body weight and mean Hb concentration during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, ratings of tolerability and adverse events (AEs).Results: Mean (± standard deviation [SD]) Hb concentration over the last 4 weeks of treatment was 11.61 ± 1.27 g/dL for patients receiving epoetin zeta, compared with 11.63 ± 1.37 g/dL for patients receiving epoetin alfa (95% c...

Comparison of the therapeutic effects of epoetin zeta and epoetin alpha in the correction of renal anaemia.

Introduction
The primary objective of the trial was to prove the therapeutic equivalence of epoetin zeta to epoetin alfa when administered subcutaneously for maintaining target hemoglobin (Hb) in patients with renal anemia on chronic hemodialysis. Additional information was provided on the safety and tolerability of epoetin zeta with particular focus on the formation of anti-erythropoietin antibodies.

Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia.

The aim of this trial was to gather data on the long-term safety of a new erythropoietin preparation (epoetin zeta), focusing on the formation of anti-erythropoietin antibodies, when administered intravenously for maintenance of target hemoglobin concentration in anemic patients with end-stage renal failure receiving chronic hemodialysis. In addition, we aimed to provide information on the efficacy of epoetin zeta under open, noncontrolled conditions. Patients received epoetin zeta intravenously, 1–3 times/week for 56 weeks (overall patient group, n=745) or 108 weeks (Bulgarian subgroup, n=164). The aim of treatment was to maintain hemoglobin values between 10.5 and 12.5 g/dL with constant epoetin dosage. Primary (safety) endpoints were the occurrence of anti-erythropoietin antibodies and the evaluation of adverse events (AEs). Secondary (efficacy) endpoints included the mean weekly dose of epoetin per kg of body weight and mean hemoglobin concentrations. No patients developed neutralizing anti-erythropoietin antibodies. The most commonly reported AEs were infections and infestations (34.1%); followed by injury, poisoning, and procedural complications (25.8%); and gastrointestinal disorders (21.9%); 37.3% of patients reported serious AEs. The hemoglobin values remained stable, with mean values after 56 weeks of 11.3–11.6 g/dL for the overall group and 11.1–11.6 g/dL for the Bulgarian subgroup. The dosage of epoetin zeta was stable throughout the course of the trial. No cases of lack of (or loss of ) efficacy were observed in the course of the trial. The evaluation of the primary endpoints provided data supporting the intravenous administration of epoetin zeta in patients with chronic renal failure. Neutralizing antibodies against erythropoietin were not detected, and there were no reports of patients with increasing erythropoietin resistance. Our results suggest that intravenous administration of epoetin zeta is effective regarding its ability to maintain stabilized hemoglobin levels within the target range of 10.5–12.5 g/dL.

Long-term safety and tolerability of epoetin zeta, administered intravenously, for maintenance treatment of renal anemia

Epoetin zeta is a recently introduced recombinant erythropoietin, designed to be biologically similar to epoetin alfa. This posthoc analysis evaluated the impact of switching patients with chronic kidney disease (CKD) on hemodialysis from epoetin alfa to epoetin zeta, or vice versa, on hemoglobin concentration, epoetin dose, and patient safety. Data were analyzed from three published trials: two 24-week randomized, double-blind (maintenance and induction) studies and a 56-week, open-label, follow-on study involving adult patients with CKD stage 5, maintained on hemodialysis, and receiving epoetin alfa or epoetin zeta. Patients had either completed and switched treatments within the maintenance study, or had completed the induction or maintenance study on epoetin alfa and then switched to, and completed at least 12 weeks of follow-up treatment on, epoetin zeta. Mean hemoglobin levels and epoetin dose were evaluated pre- (0–4 weeks before) and post- (8–12 weeks after) switch, and were considered equivalent for the two treatments if the upper and lower limits of the 95% confidence intervals (CIs) for the intraindividual differences in mean values fell within accepted limits. Overall, 481 patients were included in the analysis. Mean hemoglobin concentration was maintained at target levels (10.5–12.5 g/dL) throughout the drug switch. The mean differences in hemoglobin concentration and associated 95% CIs following the switch remained within prespecified equivalence limits (±1.0 g/dL). The 95% CIs of the mean difference in weekly epoetin dose postswitch also remained within prespecified equivalence margins (±45 IU/kg; upper limit 17.83 IU/kg, lower limit −10.91 IU/kg). Both treatments were similarly well tolerated. Our data suggest that epoetin alfa and epoetin zeta therapy can be interchanged without any clinically significant alteration in efficacy, safety, or epoetin dose, in patients with CKD on dialysis receiving stable epoetin maintenance therapy.

Rossen Koytchev

Papers

Comparison of the therapeutic effects of epoetin zeta to epoetin alfa in the maintenance phase of renal anaemia treatment

Comparison of the therapeutic effects of epoetin zeta and epoetin alpha in the correction of renal anaemia.

Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia.

Long-term safety and tolerability of epoetin zeta, administered intravenously, for maintenance treatment of renal anemia

Switching epoetin alfa and epoetin zeta in patients with renal anemia on dialysis: Posthoc analysis.