Synthesis of Stable Isotope, Tritiated, and Carbon-14 Labeled Balcinrenone.

As part of a medicinal chemistry program aimed at discovering a mineralocorticoid receptor modulator for treatment of kidney and cardiovascular indications, multiple labeled versions of the lead compound, balcinrenone (AZD9977), were prepared. Four stable isotope labeled versions of the compound were prepared for clinical bioanalysis and biological investigations. Three of these stable isotope labeled compounds were tritiated as well as the parent for biology applications and DMPK investigations. They were prepared using a standard iodination-tritiodehalogentation approach. Finally, AZD9977 was prepared in carbon-14 labeled form for preclinical and clinical applications.

Automatic Cocrystal Detection by Raman Spectral Deconvolution-Based Novelty Analysis.

Cocrystals are important molecular adducts that have many advantages as a means of modifying the physicochemical properties of active pharmaceutical ingredients, including taste masking and improved solubility, bioavailability, and stability. As a result, the discovery of new cocrystals is of great interest to commercial drug discovery programs. Time-consuming manual analysis of the large volumes of data that emerge from large-scale cocrystal screening programs of up to 1000s of preparations poses a challenge. Raman spectroscopy has been shown to discriminate between cocrystals and physical mixtures and is easy to automate, allowing rapid screening of large numbers of potential cocrystals, but the spectral features that encode the information are often subtle (e.g., slight changes in peak positions or intensities). We have employed an automated signal processing routine based on a sparse decomposition algorithm to speed up the data processing steps while maintaining the accuracy of a trained spectroscopist. We used our algorithm to screen 31 potential cocrystal preparations and found that through the use of a computationally generated threshold, we could achieve a clear classification of cocrystals and physical mixtures in less than a minute, compared to several hours manually.

Relationship between conformational flexibility and chelate cooperativity.

A family of four biscarbamates (AA) and four bisphenols (DD) were synthesized, and H-bonding interactions between all AA•DD combinations were characterized using (1)H NMR titrations in carbon tetrachloride. A chemical double mutant cycle analysis shows that there are no secondary electrostatic interactions or allosteric cooperativity in these systems, and the system therefore provides an ideal platform for investigating the relationship between chemical structure and chelate cooperativity. Effective molarities (EMs) were measured for 12 different systems, where the number of rotors in the chains connecting the two H-bond sites was varied from 5 to 20. The association constants vary by less than an order of magnitude for all 12 complexes, and the variation in EM is remarkably small (0.1-0.9 M). The results provide a relationship between EM and the number of rotors in the connecting chains (r): EM ≈ 10r(-3/2). The value of 10 M is the upper limit for the value of EM for a noncovalent intramolecular interaction. Introduction of rotors reduces the value of EM from this maximum in accord with a random walk analysis of the encounter probability of the chain ends (r(-3/2)). Noncovalent EMs never reach the very high values observed for covalent processes, which places limitations on the magnitudes of the effects that one is likely to achieve through the use of chelate cooperativity in supramolecular assembly and catalysis. On the other hand, the decrease in EM due to the introduction of conformational flexibility is less dramatic than one might expect based on the behavior of covalent systems, which limits the losses in binding affinity caused by poor preorganization of the interaction sites.