Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo

Journal of Medicinal Chemistry

Volumn 60, Issue 13, 2017, Pages 5717-5735

  Lorthiois, Edwige ^a   Anderson, Karen ^b   Vulpetti, Anna ^a   Rogel, Olivier ^a   Cumin, Frederic ^a   Ostermann, Nils ^a   Steinbacher, Stefan ^c   Mac Sweeney, Aengus ^a,e   Delgado, Omar ^b   Liao, Sha Mei ^b   Randl, Stefan ^a,d   Rüdisser, Simon ^a   Dussauge, Solene ^a   Fettis, Kamal ^a   Kieffer, Laurence ^a   De Erkenez, Andrea ^b   Yang, Louis ^b   Hartwieg, Constanze ^a   Argikar, Upendra A ^b   La Bonte, Laura R ^b   Newton, Ronald ^b   Kansara, Viral ^b   Flohr, Stefanie ^a   Hommel, Ulrich ^a   Jaffee, Bruce ^b   Maibaum, Jürgen ^a   more..

^a NOVARTIS PHARMA AG   (Switzerland)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^c PROTEROS BIOSTRUCTURES GMBH   (Germany)

^d Evonik Japan Co Ltd   (Japan)

^e ACTELION PHARMACEUTICALS LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

(1 CARBAMOYL 1H INDOL 3 YL)ACETIC ACID; 1 [2 [3 [(6 BROMOPYRIDIN 2 YL)CARBAMOYL] 2 AZABICYCLO[3.1.0]HEXAN 2 YL] 2 OXOETHYL] 1H INDAZOLE 3 CARBOXAMIDE; 2 (3 ACETYL) 1H INDAZOL 1 YL)ACETIC ACID; 2 (3 TRIFLUOROMETHOXY PHENYLCARBAMOYL) 4 METHYL PYRROLIDINE 1 CARBOXYLIC ACID TERT BUTYL ESTER; 2 AZA BICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 2 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 3 [(2 FLUORO 3 TRIFLUOROMETHYL PHENYL)AMIDE]; 2 AZA BICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 2 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 3 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; 2 AZABICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 2 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 3 [(2 FLUORO 3 TRIFLUOROMETHOXY PHENYL)AMIDE]; 2 AZABICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 2 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 3 [(3 CHLOROPHENYL)AMIDE]; 2 AZABICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 2 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 3 [(3 DIFLUOROMETHOXY PHENYL)AMIDE]; 2 AZABICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 2 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 3 [(3 METHOXY PHENYL)AMIDE]; 2 AZABICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 3 [(3 BROMOPHENYL)AMIDE] 2 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE]; 3 AZA BICYCLO[3.1.0]HEXANE 2,3 DICARBOXYLIC ACID 3 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; 3 ISOCYANATO 1 METHYL 1H INDOLE; 3 ISOCYANATO INDOLE 1 CARBOXYLIC ACID AMIDE; 4 AMINO PYRROLIDINE 1,2 DICARBOXYLIC ACID 1 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]FORMATE SALT; 4 FLUORO PYRROLIDINE 1,2 DICARBOXYLIC ACID 1 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; 4 HYDROXY PYRROLIDINE 1,2 DICARBOXYLIC ACID 1 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; 4 METHYL PYRROLIDINE 1,2 DICARBOXYLIC ACID 1 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; 4,4 DIFLUORO PYRROLIDINE 1,2 DICARBOXYLIC ACID 1 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; COMPLEMENT FACTOR D; COMPLEMENT INHIBITOR; DICLOFENAC; PIPERIDINE 1,2 DICARBOXYLIC ACID 1 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; PYRROLIDINE 1,2 DICARBOXYLIC ACID 1 [(1 CARBAMOYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; PYRROLIDINE 1,2 DICARBOXYLIC ACID 1 [(1 METHYL 1H INDOL 3 YL)AMIDE] 2 [(3 TRIFLUOROMETHOXY PHENYL)AMIDE]; S1 SERINE PROTEASE FACTOR D INHIBITOR; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; COMPLEMENT MEMBRANE ATTACK COMPLEX; PROLINE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; COMPLEMENT ACTIVATION; COMPLEMENT ALTERNATIVE PATHWAY; COMPLEMENT INHIBITION; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DISPOSITION; DRUG DISTRIBUTION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; EX VIVO STUDY; EYE TISSUE; HAPLORHINI; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MACACA FASCICULARIS; MALE; MOUSE; NONHUMAN; PHARMACODYNAMICS; RAT; RETINAL NEUROEPITHELIAL LAYER; SINGLE DRUG DOSE; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; ATYPICAL HEMOLYTIC UREMIC SYNDROME; DRUG EFFECTS; FEMALE; IMMUNOLOGY; MACULAR DEGENERATION; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; ANIMALS; ATYPICAL HEMOLYTIC UREMIC SYNDROME; COMPLEMENT FACTOR D; COMPLEMENT MEMBRANE ATTACK COMPLEX; COMPLEMENT PATHWAY, ALTERNATIVE; FEMALE; HAPLORHINI; HUMANS; MACACA FASCICULARIS; MACULAR DEGENERATION; MALE; MICE; PROLINE;

EID: 85023771380     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.7b00425     Document Type: Article

References (40)

1. Ricklin, D.; Hajishengallis, G.; Yang, K.; Lambris, J. D. Complement: a key system for immune surveillance and homeostasis Nat. Immunol. 2010, 11, 785-797 10.1038/ni.1923
2. Zarkadis, I. K.; Mastellos, D.; Lambris, J. D. Phylogenetic aspects of the complement system Dev. Comp. Immunol. 2001, 25, 745-762 10.1016/S0145-305X(01)00034-9
3. Ricklin, D.; Lambris, J. D. Complement-targeted therapeutics Nat. Biotechnol. 2007, 25, 1265-1275 10.1038/nbt1342
4. Volanakis, J. E.; Narayana, S. V. L. Complement factor D, a novel serine protease Protein Sci. 1996, 5, 553-564 10.1002/pro.5560050401
5. Jing, H.; Babu, Y. S.; Moore, D.; Kilpatrick, J. M.; Liu, X.-Y.; Volanakis, J. E.; Narayana, S. V. L. Structures of native and complexed complement factor D: Implications of the atypical His57 conformation and self-inhibitory loop in the regulation of specific serine protease activity J. Mol. Biol. 1998, 282, 1061-1081 10.1006/jmbi.1998.2089
6. Jing, H.; Macon, K. J.; Moore, D.; DeLucas, L. J.; Volanakis, J. E.; Narayana, S. V. L. Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D EMBO J. 1999, 18, 804-814 10.1093/emboj/18.4.804
7. Taylor, F. R.; Bixler, S. A.; Budman, J. I.; Wen, D.; Karpusas, M.; Ryan, S. T.; Jaworski, G. J.; Safari-Fard, A.; Pollard, S.; Whitty, A. Induced fit activation mechanism of the exceptionally specific serine protease, Complement Factor D Biochemistry 1999, 38, 2849-2859 10.1021/bi982140f
8. Forneris, F.; Ricklin, D.; Wu, J.; Tzekou, A.; Wallace, R. S.; Lambris, J. D.; Gros, P. Structures of C3b in complex with factors B and D give insight into complement convertase formation Science 2010, 330, 1816-1820 10.1126/science.1195821
9. Maibaum, J.; Liao, S.-M.; Vulpetti, A.; Ostermann, N.; Randl, S.; Rudisser, S.; Lorthiois, E.; Erbel, P.; Kinzel, B.; Kolb, F. A.; Barbieri, S.; Wagner, J.; Durand, C.; Fettis, K.; Dussauge, S.; Hughes, N.; Delgado, O.; Hommel, U.; Gould, T.; Mac Sweeney, A.; Gerhartz, B.; Cumin, F.; Flohr, S.; Schubart, A.; Jaffee, B.; Harrison, R.; Risitano, A. M.; Eder, J.; Anderson, K. Small-molecule factor D inhibitors targeting the alternative complement pathway Nat. Chem. Biol. 2016, 12, 1105-1110 10.1038/nchembio.2208
10. Vulpetti, A.; Randl, S.; Rüdisser, S.; Ostermann, N.; Erbel, P.; Mac Sweeney, A.; Zoller, T.; Salem, B.; Gerhartz, B.; Cumin, F.; Hommel, U.; Dalvit, C.; Lorthiois, E.; Maibaum, J. Structure-based library design and fragment screening for the identification of reversible complement Factor D protease inhibitors J. Med. Chem. 2017, 60, 1946-1958 10.1021/acs.jmedchem.6b01684
11. Morikis, D.; Lambris, J. D. Structural aspects and design of low-molecular-mass complement inhibitors Biochem. Soc. Trans. 2002, 30, 1026-1036 and references cited therein 10.1042/bst0301026
12. Katschke, K. J., Jr.; Wu, P.; Ganesan, R.; Kelley, R. F.; Mathieu, M. A.; Hass, P. E.; Murray, J.; Kirchhofer, D.; Wiesmann, C.; van Lookeren Campagne, M. Inhibiting alternative pathway complement activation by targeting the factor D exosite J. Biol. Chem. 2012, 287, 12886-12892 10.1074/jbc.M112.345082
13. Mastellos, D. C.; Yancopoulou, D.; Kokkinos, P.; Huber-Lang, M.; Hajishengallis, G.; Biglarnia, A. R.; Lupu, F.; Nilsson, B.; Risitano, A. M.; Ricklin, D.; Lambris, J. D. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention Eur. J. Clin. Invest. 2015, 45, 423-440 10.1111/eci.12419
14. Yuan, X.; Gavriilaki, E.; Baines, A. C.; Thanassi, J. A.; Yang, G.; Podos, S. D.; Huang, Y.; Huang, M.; Brodsky, R. A. Small-molecule Factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome Haematologica 2017, 102, 466-475 10.3324/haematol.2016.153312
15. Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A. The maximal affinity of ligands Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 9997-10002 10.1073/pnas.96.18.9997
16. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection Drug Discovery Today 2004, 9, 430-431 10.1016/S1359-6446(04)03069-7
17. Abad-Zapatero, C.; Metz, J. T. Ligand efficiency indices as guideposts for drug discovery Drug Discovery Today 2005, 10, 464-469 10.1016/S1359-6446(05)03386-6
18. Reynolds, C. H.; Bembenek, S. D.; Tounge, B. A. The role of molecular size in ligand efficiency Bioorg. Med. Chem. Lett. 2007, 17, 4258-4261 10.1016/j.bmcl.2007.05.038
19. Leeson, P. D.; Springthorpe, B. The influence of drug like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890 10.1038/nrd2445
20. Perola, E. An analysis of binding efficiencies of drugs and their leads in successful drug discovery programs J. Med. Chem. 2010, 53, 2986-2997 10.1021/jm100118x
21. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.; Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: a lipophilic efficiency (LipE) analysis Bioorg. Med. Chem. Lett. 2009, 19, 4406-4409 10.1016/j.bmcl.2009.05.062
22. Shultz, M. D. The thermodynamic basis for the use of lipophilic efficiency in enthalpic optimization Bioorg. Med. Chem. Lett. 2013, 23, 5992-6000 10.1016/j.bmcl.2013.08.030
23. Escobar, P. A.; Kemper, R. A.; Tarca, J.; Nicolette, J.; Kenyon, M.; Glowienke, S.; Sawant, S. G.; Christensen, J.; Johnson, T. E.; McKnight, C.; Ward, G.; Galloway, S. M.; Custer, L.; Gocke, E.; O'Donovan, M. R.; Braun, K.; Snyder, R. D.; Mahadevan, B. Bacterial mutagenicity screening in the pharmaceutical industry Mutat. Res., Rev. Mutat. Res. 2013, 752, 99-118 10.1016/j.mrrev.2012.12.002
24. Frieauff, W.; Martus, H. J.; Suter, W.; Elhajouji, A. Automatic analysis of the micronucleus test in primary human lymphocytes using image analysis Mutagenesis 2013, 28, 15-23 10.1093/mutage/ges047
25. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry J. Med. Chem. 2015, 58, 8315-8359 and references cited therein 10.1021/acs.jmedchem.5b00258
26. Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in medicinal chemistry ChemBioChem 2004, 5, 637-643 10.1002/cbic.200301023
27. Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition Science 2007, 317, 1881-1886 10.1126/science.1131943
28. Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in drug design: A case study with fluoroanisoles ChemMedChem 2015, 10, 715-726 10.1002/cmdc.201402555
29. Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Halogen bonds in biological molecules Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 16789-16794 10.1073/pnas.0407607101
30. Voth, A. R.; Khuu, P.; Oishi, K.; Ho, P. S. Halogen bonds as orthogonal molecular interactions to hydrogen bonds Nat. Chem. 2009, 1, 74-79 10.1038/nchem.112
31. Wilcken, R.; Zimmermann, M. O.; Lange, A.; Joerger, A. C.; Boeckler, F. M. Principles and applications of halogen bonding in medicinal chemistry and chemical biology J. Med. Chem. 2013, 56, 1363-1388 10.1021/jm3012068
32. Parisini, E.; Metrangolo, P.; Pilati, T.; Resnati, G.; Terraneo, G. Halogen bonding in halocarbon-protein complexes: a structural survey Chem. Soc. Rev. 2011, 40, 2267-2278 10.1039/c0cs00177e
33. Dalvit, C.; Vulpetti, A. Intermolecular and intramolecular hydrogen bonds involving fluorine atoms: Implications for recognition, selectivity, and chemical properties ChemMedChem 2012, 7, 262-272 10.1002/cmdc.201100483
34. Riley, K. E.; Murray, J. S.; Fanfrlik, J.; Rezac, J.; Sola, R. J.; Concha, M. C.; Ramos, F. M.; Politzer, P. Halogen bond tunability I: the effects of aromatic fluorine substitution on the strengths of halogen-bonding interactions involving chlorine, bromine, and iodine J. Mol. Model. 2011, 17, 3309-3318 10.1007/s00894-011-1015-6
35. Riley, K. E.; Murray, J. S.; Fanfrlik, J.; Rezac, J.; Sola, R. J.; Concha, M. C.; Ramos, F. M.; Politzer, P. Halogen bond tunability II: the varying roles of electrostatic and dispersion contributions to attraction in halogen bonds J. Mol. Model. 2013, 19, 4651-4659 10.1007/s00894-012-1428-x
36. Riley, K. E.; Hobza, P. Strength and character of halogen bonds in protein-ligand complexes Cryst. Growth Des. 2011, 11, 4272-4278 10.1021/cg200882f
37. Yang, C.-Y.; Phillips, J. G.; Stuckey, J. A.; Bai, L.; Sun, H.; Delproposto, J.; Brown, W. C.; Chinnaswamy, K. Buried hydrogen bond interactions contribute to the high potency of complement factor D inhibitors ACS Med. Chem. Lett. 2016, 7, 1092-1096 10.1021/acsmedchemlett.6b00299
38. Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb J. Med. Chem. 2008, 51, 817-834 10.1021/jm701122q
39. Conrow, R. E.; Dean, W. D. Diazidomethane explosion Org. Process Res. Dev. 2008, 12, 1285-1286 10.1021/op8000977
40. Schramm, E. C.; Clark, S. J.; Triebwasser, M. P.; Raychaudhuri, S.; Seddon, J. M.; Atkinson, J. P. Genetic variants in the complement system predisposing to age-related macular degeneration: a review Mol. Immunol. 2014, 61, 118-125 10.1016/j.molimm.2014.06.032