5-Trifluoromethyl-pyridine-2-sulfonic acid {3-[1-((R)-4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)-propyl]-phenyl}-amide

ID: ALA222559

Max Phase: Approved

First Approval: 2005

Molecular Formula: C31H33F3N2O5S

Molecular Weight: 602.68

Molecule Type: Small molecule

Names and Identifiers

Synonyms: Tipranavir | U-140690

Synonyms from Alternative Forms(3): Tipranavir disodium | Tipranavir sodium | PNU-140690E

Trade Names(1): Aptivus

Canonical SMILES:  CCC[C@@]1(CCc2ccccc2)CC(O)=C([C@H](CC)c2cccc(NS(=O)(=O)c3ccc(C(F)(F)F)cn3)c2)C(=O)O1

Standard InChI:  InChI=1S/C31H33F3N2O5S/c1-3-16-30(17-15-21-9-6-5-7-10-21)19-26(37)28(29(38)41-30)25(4-2)22-11-8-12-24(18-22)36-42(39,40)27-14-13-23(20-35-27)31(32,33)34/h5-14,18,20,25,36-37H,3-4,15-17,19H2,1-2H3/t25-,30-/m1/s1

Standard InChI Key:  SUJUHGSWHZTSEU-FYBSXPHGSA-N

Molfile:  

     RDKit          2D

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    1.2167    0.2458    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2000   -0.5792    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.9292    0.6458    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -5.6208    1.6208    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.9042   -1.0042    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -3.1458    1.5958    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.7958    1.5958    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.3333    0.7458    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.5125    0.6625    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.5458    0.8833    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.6292   -0.6125    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.6375    0.2208    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.2125    0.2750    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2875    2.3958    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -1.4875    1.5458    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.4792   -0.9792    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -4.3708    0.8750    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.9125    0.7000    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.6333    0.3083    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.3833    2.3083    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.5583    2.3083    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.9375    1.4750    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -6.0000    2.3458    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   -6.2167    1.0583    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   -5.8583    0.8333    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    3.2792   -1.1042    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1792   -1.9250    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8375   -2.4250    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.2333   -0.5542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.5292    1.4958    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.4417   -0.7042    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.9625   -0.9500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.6625   -0.5125    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5917   -2.1042    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.7292   -3.2417    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.7667   -1.4542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2542    1.8958    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5792   -1.5500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.3792   -3.7417    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.2417   -2.6000    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.1417   -3.4167    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  2 10  1  0
  3  2  1  0
  4  2  2  0
  5  8  1  0
  6  3  1  0
  7  1  1  0
  8 21  2  0
  9  1  1  0
 10 14  1  0
 11  7  1  0
 12 13  1  0
 13  4  1  0
 14 19  2  0
 15  1  2  0
 16  1  2  0
 17  3  2  0
 18 11  2  0
 19 20  1  0
 20  9  1  0
 21 22  1  0
 22  7  2  0
 23  4  1  0
 24  5  1  0
 25  5  1  0
 26  5  1  0
 12 27  1  1
 28 27  1  0
 29 28  1  0
 30 33  2  0
 10 31  1  1
 32 12  1  0
 33 34  1  0
 34 20  2  0
 35 29  1  0
 36 29  2  0
 37 32  1  0
 38 31  1  0
 39 37  1  0
 40 36  1  0
 41 35  2  0
 42 40  2  0
 18  8  1  0
 14 30  1  0
  6 12  1  0
 41 42  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA222559

   TIPRANAVIR

2. Alternative Forms:

   

   ALA222559

   14c-Tipranavir
3. 

   ALA222559

   TIPRANAVIR DISODIUM

Molecule Features

Natural Product: Yes

Oral: Yes

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: Yes

Chirality: Yes

Availability: Yes

Prodrug: No

Calculated Properties

Molecular Weight: 602.68

Molecular Weight (Monoisotopic): 602.2062

AlogP: 7.33

#Rotatable Bonds: 11

Polar Surface Area: 105.59

Molecular Species: ACID

HBA: 6

HBD: 2

#RO5 Violations: 2

HBA (Lipinski): 7

HBD (Lipinski): 2

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 4.43

CX Basic pKa: ┄

CX LogP: 7.14

CX LogD: 3.45

Aromatic Rings: 3

Heavy Atoms: 42

QED Weighted: 0.22

Np Likeness Score: -0.52

References

1. Turner SR, Strohbach JW, Tommasi RA, Aristoff PA, Johnson PD, Skulnick HI, Dolak LA, Seest EP, Tomich PK, Bohanon MJ, Horng MM, Lynn JC, Chong KT, Hinshaw RR, Watenpaugh KD, Janakiraman MN, Thaisrivongs S..  (1998)  Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class.,  41  (18): [PMID:9719600] [10.1021/jm9802158]

2. Thaisrivongs S, Skulnick HI, Turner SR, Strohbach JW, Tommasi RA, Johnson PD, Aristoff PA, Judge TM, Gammill RB, Morris JK, Romines KR, Chrusciel RA, Hinshaw RR, Chong KT, Tarpley WG, Poppe SM, Slade DE, Lynn JC, Horng MM, Tomich PK, Seest EP, Dolak LA, Howe WJ, Howard GM, Watenpaugh KD..  (1996)  Structure-based design of HIV protease inhibitors: sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones as non-peptidic inhibitors.,  39  (22): [PMID:8893827] [10.1021/jm960541s]

3. Garino C, Bihel F, Pietrancosta N, Laras Y, Quéléver G, Woo I, Klein P, Bain J, Boucher JL, Kraus JL..  (2005)  New 2-bromomethyl-8-substituted-benzo[c]chromen-6-ones. Synthesis and biological properties.,  15  (1): [PMID:15582426] [10.1016/j.bmcl.2004.10.018]

4. Surleraux DL, de Kock HA, Verschueren WG, Pille GM, Maes LJ, Peeters A, Vendeville S, De Meyer S, Azijn H, Pauwels R, de Bethune MP, King NM, Prabu-Jeyabalan M, Schiffer CA, Wigerinck PB..  (2005)  Design of HIV-1 protease inhibitors active on multidrug-resistant virus.,  48  (6): [PMID:15771440] [10.1021/jm049454n]

5. Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA..  (2007)  Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.,  51  (2): [PMID:17116674] [10.1128/aac.00870-06]

6. Hensen C, Hermann JC, Nam K, Ma S, Gao J, Höltje HD..  (2004)  A combined QM/MM approach to protein--ligand interactions: polarization effects of the HIV-1 protease on selected high affinity inhibitors.,  47  (27): [PMID:15615516] [10.1021/jm0497343]

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9. Pedersen JM, Matsson P, Bergström CA, Norinder U, Hoogstraate J, Artursson P..  (2008)  Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2).,  51  (11): [PMID:18457386] [10.1021/jm7015683]

10. Hazen R, Harvey R, Ferris R, Craig C, Yates P, Griffin P, Miller J, Kaldor I, Ray J, Samano V, Furfine E, Spaltenstein A, Hale M, Tung R, St Clair M, Hanlon M, Boone L..  (2007)  In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV.,  51  (9): [PMID:17620375] [10.1128/aac.00401-07]

11. Tong L, Phan TK, Robinson KL, Babusis D, Strab R, Bhoopathy S, Hidalgo IJ, Rhodes GR, Ray AS..  (2007)  Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro.,  51  (10): [PMID:17664327] [10.1128/aac.00671-07]

12. Chen L, Sabo JP, Philip E, Mao Y, Norris SH, MacGregor TR, Wruck JM, Garfinkel S, Castles M, Brinkman A, Valdez H..  (2007)  Steady-state disposition of the nonpeptidic protease inhibitor tipranavir when coadministered with ritonavir.,  51  (7): [PMID:17485497] [10.1128/aac.01115-06]

13. Dekhtyar T, Ng TI, Lu L, Masse S, DeGoey DA, Flosi WJ, Grampovnik DJ, Klein LL, Kempf DJ, Molla A..  (2008)  Characterization of a novel human immunodeficiency virus type 1 protease inhibitor, A-790742.,  52  (4): [PMID:18212102] [10.1128/aac.01132-07]

14. Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2)..  (2008)  In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.,  52  (4): [PMID:18227188] [10.1128/aac.01284-07]

15. Peatey CL, Andrews KT, Eickel N, MacDonald T, Butterworth AS, Trenholme KR, Gardiner DL, McCarthy JS, Skinner-Adams TS..  (2010)  Antimalarial asexual stage-specific and gametocytocidal activities of HIV protease inhibitors.,  54  (3): [PMID:20028821] [10.1128/aac.01512-09]

16. Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H..  (2010)  Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.,  54  (8): [PMID:20439612] [10.1128/aac.01766-09]

17. Young TP, Parkin NT, Stawiski E, Pilot-Matias T, Trinh R, Kempf DJ, Norton M..  (2010)  Prevalence, mutation patterns, and effects on protease inhibitor susceptibility of the L76V mutation in HIV-1 protease.,  54  (11): [PMID:20805393] [10.1128/aac.00906-10]

18. Parry CM, Kolli M, Myers RE, Cane PA, Schiffer C, Pillay D..  (2011)  Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity.,  55  (3): [PMID:21149628] [10.1128/aac.01228-10]

19. Unpublished dataset, 

20.  (2008)  Casarett and Doull's Toxicology The Basic Science of Poisons, 7th edition, 

21. Chen M, Vijay V, Shi Q, Liu Z, Fang H, Tong W..  (2011)  FDA-approved drug labeling for the study of drug-induced liver injury.,  16  (15-16): [PMID:21624500] [10.1016/j.drudis.2011.05.007]

22. Liu Z, Shi Q, Ding D, Kelly R, Fang H, Tong W..  (2011)  Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps).,  7  (12): [PMID:22194678] [10.1371/journal.pcbi.1002310]

23. USP Dictionary of USAN and International Names (2010 edition) and USAN registrations 2007-date, 

24. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P..  (2012)  Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.,  55  (10): [PMID:22541068] [10.1021/jm300212s]

25. PubChem BioAssay data set, 

26. Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A..  (2013)  Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.,  56  (21): [PMID:24088053] [10.1021/jm400813y]

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28. British National Formulary (72nd edition), 

29. Chen M, Suzuki A, Thakkar S, Yu K, Hu C, Tong W..  (2016)  DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans.,  21  (4): [PMID:26948801] [10.1016/j.drudis.2016.02.015]

30. Unpublished dataset, 

31. Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek.  (2020)  Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection,  [10.21203/rs.3.rs-23951/v1]

32. Katie Heiser, Peter F. McLean, Chadwick T. Davis, Ben Fogelson, Hannah B. Gordon, Pamela Jacobson, Brett Hurst, Ben Miller, Ronald W. Alfa, Berton A. Earnshaw, Mason L. Victors, Yolanda T. Chong, Imran S. Haque, Adeline S. Low, Christopher C. Gibson.  (2020)  Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2,  [10.1101/2020.04.21.054387]

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34. Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani.  (2020)  Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen,  [10.6019/CHEMBL4495564]

35. Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen.  (2020)  Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort,  [10.6019/CHEMBL4495565]

36. Ellen Van Damme.  (2021)  Screening of ~5500 FDA-approved drugs and clinical candidates for anti-SARS-CoV-2 activity,  [10.6019/CHEMBL4651402]

37. Ghahremanpour MM,Tirado-Rives J,Deshmukh M,Ippolito JA,Zhang CH,Cabeza de Vaca I,Liosi ME,Anderson KS,Jorgensen WL.  (2020)  Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2.,  11  (12.0): [PMID:33324471] [10.1021/acsmedchemlett.0c00521]

38. Bernhard Ellinger, Justus Dick, Vanessa Lage-Rupprecht, Bruce Schultz, Andrea Zaliani, Marcin Namysl, Stephan Gebel, Ole Pless, Jeanette Reinshagen, Christian Ebeling, Alexander Esser, Marc Jacobs, Carsten Claussen, and Martin Hofmann-Apitius.  (2021)  HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators,  [10.6019/CHEMBL4808148]

39. Hassan MZ, Osman H, Ali MA, Ahsan MJ..  (2016)  Therapeutic potential of coumarins as antiviral agents.,  123  [PMID:27484512] [10.1016/j.ejmech.2016.07.056]

40. Sutherland JJ, Yonchev D, Fekete A, Urban L..  (2023)  A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs.,  14  (1): [PMID:37468498] [10.1038/s41467-023-40064-9]

41. European Medicines Agency, 

Source

Source(11):

• Scientific Literature
• PubChem BioAssays
• Clinical Candidates
• FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)
• USP Dictionary of USAN and International Drug Names
• WHO Anatomical Therapeutic Chemical Classification
• British National Formulary
• SARS-CoV-2 Screening Data 2020-21
• IMI-CARE SARS-CoV-2 Data
• Fraunhofer HDAC6
• European Medicines Agency