Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

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.

/pdf/deuterium-and-tritium-labelled-compounds-applications-in-the-1q739u5gx2.pdf

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

Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly

A number of drugs have been withdrawn from the market or severely restricted in their use because of unexpected toxicities that become apparent only after the launch of new drug entities. Circumstantial evidence suggests that, in most cases, reactive metabolites are responsible for these unexpected toxicities. In this review, a general overview of the types of reactive metabolites and the consequences of their formation are presented. The current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these procedures will be discussed. Reasonable reasons for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development. This will, in turn, help us to design and bring safer drugs to the market.

/pdf/deleterious-effects-of-reactive-metabolites-1wpav452u6.pdf

Deleterious effects of reactive metabolites.

The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C-F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds.

The syntheses of tritium labeled (S)-3-(5-chloro-2-[OC3H3]methoxyphenyl-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-1H-indol-2-one, and carbon-14 (S)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-[2,3-14C2] indol-2-one are reported. The 3H-labeled compound was prepared in a two-step synthesis from C3H3I. The final product was purified via chiral HPLC to yield the desired enantiomer in a 4% radiochemical yield and a specific activity of 60 Ci/mmol. The 14C-labeled compound was prepared in a four-step synthesis from diethyl [carboxylate-14C1,2] oxalate. The final product was purified via chiral HPLC to yield the desired enantiomer in a 20% radiochemical yield and a specific activity of 28.4 μCi/mg. Copyright © 2002 John Wiley & Sons, Ltd.

Synthesis of 3H and 14C labeled (S)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one, maxipost™. An agent for post-stroke neuroprotection

A reliable synthesis of 14C labeled 6-hydroxy-buspirone is described. The molecule belongs to a unique class of compounds with the potential for anxiolytic activity. A radiolabeled analog was prepared to support the development of 6-hydroxy-buspirone. Specifically, a labeled variant was designed to meet the requirements of a human adsorption-distribution-metabolism-elimination (ADME) study. Multiple 14C labels were needed to fully track the potential metabolic transformation of the molecule. Labeled 6-hydroxy-buspirone was prepared by oxidation of separately labeled versions of [14C]buspirone. The final product was isolated in reasonable yield with a radiochemical purity of 99.8%. Copyright © 2007 John Wiley & Sons, Ltd.

Synthesis of the anxiolytic agent [14C] 6-hydroxy-buspirone for use in a human ADME study

A facile and efficient synthesis of d3-labelled Reyataz™ is described. The key step of synthesis involved the coupling of N-(d3-methoxycarbonyl)-L-tert-leucine 2b with an advanced chiral non-racemic building block 4. The latter was synthesized in 4 steps from the readily accessible hydrazine derivative 8. Copyright © 2005 John Wiley & Sons, Ltd.

A facile and efficient synthesis of d3‐labelled Reyataz™

Entecavir, labeled as 1H-[13C4]purin-6(9H)-one, was prepared from commercially available [13C]guanidine HCl, 1 and diethyl [1,2,3-13C3]malonate, 2. The reagents were condensed together to give 2-amino-4,6-dichloro[2,4,5,6-13C4]pyrimidine 3, which in turn was coupled to an optically active amino cyclopentanol derivative, 9. A further sequence of eight reaction steps completed the constructions of the purine ring system and the exocyclic olefin attachment on the cyclic pentyl portion, 18. The removal of the methoxide and benzyl protecting groups gave [13C4]entecavir, 20 in an overall yield of 6.8%. The chemical purity of the title compound was determined by HPLC to be 99.23%. The percent isotopic [13C4] abundance was found by mass spectral analysis to be 96.7%. No detectable level of the unlabeled entecavir was found by LC-MS analysis. Copyright © 2009 John Wiley & Sons, Ltd.

Synthesis of [13C4]Baraclude® (entecavir)

Inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) is an effective method of lowering plasma low-density lipoprotein cholesterol levels. Hemi-calcium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (1) is a cholesterol-lowering statin drug that effectively inhibits HMGR. An important step in the development of this compound was the synthesis of a carbon-14-labeled analog for use in preclinical absorption, distribution, metabolism and excretion studies.



The synthesis of a carbon-14-labeled analog of the cholesterol-lowering statin drug 1 is described. The carbon-14-labeled compound [14C]-1 was prepared in 11 steps from [14C]-labeled urea. The overall radiochemical yield for the synthesis was 22% and the radiochemical purity of [14C]-1 was 99.9% immediately after synthesis. It was found that [14C]-1 with a specific activity of 43.2 µCi/mg decomposed at a rate of about 1.9%/month when stored at −78°C under argon. Three samples of [14C]-1 were prepared to study the chemical stability of the molecule. One sample had a specific activity of 3.8 µCi/mg and the other two contained radical inhibitors, L-ascorbic acid (1% by weight, specific activity of 10.5 µCi/mg) or BHT (1% by weight, specific activity of 9.8 µCi/mg). For these samples the decomposition rates were decreased to 0.5%/month, 0.2%/month and 0.1%/month, respectively. Copyright © 2010 John Wiley & Sons, Ltd.

Synthesis and stability of a carbon-14-labeled 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor

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