Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

A Spectroscopic and Diffractometric Study of Polymorphism in Ethyl 3‑{3-[((2<i>R</i>)‑3-{[2-(2,3-dihydro‑1<i>H</i>‑inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl}propanoate Hydrochloride

Two polymorphic forms of ethyl 3-{3-[((2<i>R</i>)-3-{[2-(2,3-dihydro-1<i>H</i>-inden-2-yl)-1,1-dimethylethyl]­amino}-2-hydroxypropyl)­oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the ¹H, ¹³C, ¹⁵N, ¹⁹F, and ³⁵Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combined results, particularly the results obtained from X-ray diffraction analysis, ¹³C, ¹⁵N, and ³⁵Cl SSNMR, and fluorescence spectroscopy, are consistent with the more thermodynamically stable form having a structure that is an extended, perturbed superstructure of the less stable form

A Spectroscopic and Diffractometric Study of Polymorphism in Ethyl 3‑{3-[((2<i>R</i>)‑3-{[2-(2,3-dihydro‑1<i>H</i>‑inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl}propanoate Hydrochloride

Two polymorphic forms of ethyl 3-{3-[((2<i>R</i>)-3-{[2-(2,3-dihydro-1<i>H</i>-inden-2-yl)-1,1-dimethylethyl]­amino}-2-hydroxypropyl)­oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the ¹H, ¹³C, ¹⁵N, ¹⁹F, and ³⁵Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combined results, particularly the results obtained from X-ray diffraction analysis, ¹³C, ¹⁵N, and ³⁵Cl SSNMR, and fluorescence spectroscopy, are consistent with the more thermodynamically stable form having a structure that is an extended, perturbed superstructure of the less stable form

A Spectroscopic and Diffractometric Study of Polymorphism in Ethyl 3‑{3-[((2<i>R</i>)‑3-{[2-(2,3-dihydro‑1<i>H</i>‑inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl}propanoate Hydrochloride

Two polymorphic forms of ethyl 3-{3-[((2<i>R</i>)-3-{[2-(2,3-dihydro-1<i>H</i>-inden-2-yl)-1,1-dimethylethyl]­amino}-2-hydroxypropyl)­oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the ¹H, ¹³C, ¹⁵N, ¹⁹F, and ³⁵Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combined results, particularly the results obtained from X-ray diffraction analysis, ¹³C, ¹⁵N, and ³⁵Cl SSNMR, and fluorescence spectroscopy, are consistent with the more thermodynamically stable form having a structure that is an extended, perturbed superstructure of the less stable form

Solid-State NMR Analysis of a Complex Crystalline Phase of Ronacaleret Hydrochloride

A crystalline phase of the pharmaceutical compound ronacaleret hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) spectroscopy and single-crystal X-ray diffraction. The crystal structure is determined to contain two independent cationic molecules and chloride anions in the asymmetric unit, which combine with the covalent structure of the molecule to yield complex SSNMR spectra. Experimental approaches based on dipolar correlation, chemical shift tensor analysis, and quadrupolar interaction analysis are employed to obtain detailed information about this phase. Density functional theory (DFT) calculations are used to predict chemical shielding and electric field gradient (EFG) parameters for comparison with experiment. ¹H SSNMR experiments performed at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling provide information about hydrogen bonding and molecular connectivity that can be related to the crystal structure. ¹⁹F and ¹³C assignments for the <i>Z</i>′ = 2 structure are obtained using DFT calculations, ¹⁹F homonuclear dipolar correlation, and ¹³C–¹⁹F heteronuclear dipolar correlation experiments. ³⁵Cl MAS experiments at 16.4 T observe two chlorine sites that are assigned using calculated chemical shielding and EFG parameters. SSNMR dipolar correlation experiments are used to extract ¹H–¹³C, ¹H–¹⁵N, ¹H–¹⁹F, ¹³C–¹⁹F, and ¹H–³⁵Cl through-space connectivity information for many positions of interest. The results allow for the evaluation of the performance of a suite of SSNMR experiments and computational approaches as applied to a complex but typical pharmaceutical solid phase

Evaluating a Crystal Energy Landscape in the Context of Industrial Polymorph Screening

To evaluate how the calculation of a crystal energy landscape can be used in the solid-form screening of pharmaceuticals, a Knowledge Transfer Secondment between GlaxoSmithKline (GSK) and University College London was established to carry out computational crystal structure prediction (CSP) and further guided experimentation on a molecule from GSK’s compound collection. The molecule chosen was 6-[(5-chloro-2-([(4-chloro-2-fluorophenyl)­methyl]­oxy)­phenyl)­methyl]-2-pyridinecarboxylic acid (GSK269984B) since the preliminary thermodynamic form screening had only identified one anhydrate, Form I. The calculations confirmed that Form I is the most thermodynamically stable form. The thermodynamically competitive computed structures all had very different conformations of GSK269984B, and further experiments were designed to attempt to generate these conformations in solution and hence the crystalline solid. The experimental screening generated four novel solvates which all eventually transformed to Form I, two of which could also be structurally characterized by single crystal X-ray diffraction. The molecular conformation (apart from the position of the polar proton) in all three crystal structures was, however, very similar. GSK269984B appears to have an unusually small number of solid forms because there is no kinetic barrier to crystallizing in the most stable conformation which corresponds to the most thermodynamically stable and densely packed structure