Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119.

A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.

Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors.

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.

Correlating particle hardness with powder compaction performance.

Assessing particle mechanical properties of pharmaceutical materials quickly and with little material can be very important to early stages of pharmaceutical research. In this study, a wide range of pharmaceutical materials were studied using atomic force microscopy (AFM) nanoindentation. A significant amount of particle hardness and elastic modulus data were provided. Moreover, powder compact mechanical properties of these materials were investigated in order to build correlation between the particle hardness and powder compaction performance. It was found that the materials with very low or high particle hardness most likely exhibit poor compaction performance while the materials with medium particle hardness usually have good compaction behavior. Additionally, the results from this study enriched Hiestand's special case concept on particle hardness and powder compaction performance. This study suggests that the use of AFM nanoindentation can help to screen mechanical properties of pharmaceutical materials at early development stages of pharmaceutical research.

C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization.

Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.

Estimating the refractive index of pharmaceutical solids using predictive methods.

Refractive index is a basic physical property of pharmaceutical solids. In this paper, the refractive index values of 424 pharmaceutical solids from the literature were surveyed. It was found that the refractive index values exhibit a normal distribution with an overall mean value of 1.603. The Eisenlohr and Vogel methods developed for organic liquids were employed to estimate the refractive index for pharmaceutical solids. The estimated results were compared with experimentally measured values determined by polarized light microscopy. Both Eisenlohr and Vogel R(D) methods agreed very well with the measured mean refractive index values from the literature with an average absolute percent error of 1.22% and 1.25%, respectively. The evaluation for in-house measurements for Pfizer active pharmaceutical ingredients showed larger differences between the calculated and measured values. The results indicate that the Eisenlohr and Vogel R(D) methods can provide fast and accurate results for predicting the refractive index of pharmaceutical solids.

Evaluating particle hardness of pharmaceutical solids using AFM nanoindentation.

Understanding mechanical properties of pharmaceutical solids at the submicron scale can be very important to pharmaceutical research & development. In this paper, the hardness of individual particles of various pharmaceutical solids including sucrose, lactose, ascorbic acid, and ibuprofen was quantified using the atomic force microscopy (AFM) nanoindentation. Effects of data variation and indentation size or peak load on hardness are evaluated. The results show acceptable reproducibility and indicate that data variation may be primarily from the inhomogeneous nature of the samples. Different extents of indentation size or peak load effect on hardness were observed for the samples. With consideration of both data variation and indentation size effects, the hardness values of different samples were compared at similar contact depths or peak loads. The hardness ranked as: ascorbic acid>sucrose>lactose approximately ibuprofen, at contact depths from approximately 40 to 400 nm or peak loads ranging from approximately 16 to 70 microN. Additionally, the potential implication of particle hardness to compact hardness and tableting performance was discussed.