RNA Polymerase · November 24, 2021

The pharmacokinetics of macrocycle 19 was also explored 2; SD 0

The pharmacokinetics of macrocycle 19 was also explored 2; SD 0.45)b Open in a separate window aCompound measured as 4.5 once. bND = compound not selected for synthesis. Alternative aryl clearance (mL?minC1?kgC1)Mic??(human, 0.40 0.40minipig,1.630.92rat)0.48 0.46Hep??(human, 0.45 0.45minipig, 0.89 0.89rat) 0.80 0.80 Open in a separate window aCompound measured as 4.5 on one occasion. bCompound measured as 4.5 on three occasions; SD 0.32 (enzyme assays); SD 0.51 (cellular assay). cIFN inhibition in CytoStim-stimulated whole blood assay. As previously stated, macrocycle 19 exhibits increased potency and ligand efficiency compared with progenitor 18. stated, macrocycle 19 exhibits increased potency and ligand efficiency compared with progenitor 18. This also translates into a more modest increase in whole blood potency. It was expected that macrocycle 19 would have similar selectivity over NOX1 the closely related PI3K isoforms; however, a trend toward slightly improved selectivity was observed. This is possibly due to the restricted conformations of the macrocycle. Macrocycle 19 is more lipophilic than progenitor 18 and therefore has a lower lipophilic efficiency (LipE), probably due to the decreased ability to hydrogen bond within the restricted template. This is reflected in the measured pclearances close to the lower limit of the hepatocyte assay threshold across species. The lipophilicity does result in an increase in plasma protein binding; however, this still falls within acceptable ranges for both compounds. In summary, although it is more lipophilic with a lower LiPE, macrocycle 19 does not exhibit many of the associated poor developability properties.23 Given that the clearance data showed low clearance, both of the compounds were advanced into a rat PK study to further evaluate the differences in clearance (Table 4). Table 4 Intravenous Rat PK Data for Compounds 18 and 19 Cl (mL?minC1?kgC1)23312.3Vdss?(L?kgC1)8.51.8half?life?(h)0.601.5predicted clearance in the rat compared with the progenitor compound, suggesting that the macrocycle could be suitable for oral delivery. Pleasingly, on calculating the unbound clearance using a validated biomimetic model for predicting the unbound human fraction (clearance shown with key exemplars. The analysis of the thermodynamics of binding for one pair of compounds also highlights the entropic advantage of macrocyclization. These data further support macrocyclization as an attractive strategy for lead optimization. Acknowledgments We thank the EPSRC for funding via Prosperity Partnership EP/S035990/1. We thank members of Screening, Profiling and Mechanistic Biology, GSK for screening; members of Protein & Cellular Sciences, GSK for protein production; and members of Discovery Analytical, GSK for physicochemical profiling. Glossary AbbreviationsPI3Kphosphoinositide 3-kinaseLEligand efficiencyNDnot determinedIFNinterferon gammaSPRsurface plasmon resonanceCLNDchemiluminescent nitrogen detectionAMPartificial membrane permeabilityHSAhuman serum albuminAGP-1-glycoproteinhhumanmpminipigrratRuPhos2-dicyclohexylphosphino-2,6-diisopropoxybiphenylPIP2Pphosophatidylinositol 4,5-bisphosphatePIP3phosophatidylinositol 3,4,5-trisphosphateVdsssteady-state volume of distributionClunboundunbound clearanceCMRcalculated molar refractivityDCMdichloromethanedbadibenzylideneacetonePKpharmacokinetics Supporting Information Available The Supporting Senktide Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00061. Synthetic procedures and characterization of PI3K inhibitors, PI3K assay data, conformational search results, and SPR data for compounds 18 and 19 and PI3K crystallography methods and data statistics for compounds Senktide 1, 18, and 19 (PDF) Accession Codes Coordinates have been deposited with the Protein Data Bank (compound 1: 6ZAA, compound 18: 6ZAC; compound 19: 6ZAD). Author Present Address J.A.S. and C.J.H.: Charles Senktide River Laboratories, Saffron Walden, Essex, CB10 1XL, U.K. Author Present Address D.A.T.: Arctoris, 120 East Olympic Avenue, Milton Park, Abingdon, OX14 4SA, U.K. Author Contributions All authors have given approval to the final version of the manuscript. Notes The authors declare the following competing financial interest(s): All authors except J.A.S and C.J. were employees of GlaxoSmithKline at the time the work was carried out. Notes All animal studies were ethically reviewed and carried out in accordance with the Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals. Supplementary Material ml0c00061_si_001.pdf(1.4M, pdf).