5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene

ID: ALA1076903

PubChem CID: 5310966

Max Phase: Approved

First Approval: 2006

Molecular Formula: C13H13N3

Molecular Weight: 211.27

Molecule Type: Small molecule

Names and Identifiers

Synonyms: Varenicline | CP-526,555 | CP-526555 | Varenicline|vareniclina|vareniclinum|CP 526555|UNII-W6HS99O8ZO|W6HS99O8ZO|CHEBI:84500|HSDB 7591|7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino(2,3-h)(3)benzazepine|CP-526,555|DTXSID70891447|VARENICLINE (MART.)|VARENICLINE [MART.]|(1R,12S)-5,8,14-triazatetracyclo[10.3.1.0^{2,11}.0^{4,9}]hexadeca-2(11),3,5,7,9-pentaene|7,8,9,10-tetrahydro-6h-6,10-methanoazepino[4,5-g]quinoxaline|7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine|7,8,9,10-TETRAHYDShow More⌵

Synonyms from Alternative Forms(6): Varenicline tartrate | Tyrvaya | CP-526,555-18 | CP-526555-18 | Champix | Chantix

Canonical SMILES:  c1cnc2cc3c(cc2n1)[C@@H]1CNC[C@H]3C1

Standard InChI:  InChI=1S/C13H13N3/c1-2-16-13-5-11-9-3-8(6-14-7-9)10(11)4-12(13)15-1/h1-2,4-5,8-9,14H,3,6-7H2/t8-,9+

Standard InChI Key:  JQSHBVHOMNKWFT-DTORHVGOSA-N

Molfile:  

     RDKit          2D

 18 21  0  0  0  0  0  0  0  0999 V2000
   -1.7909   -5.7671    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2262   -5.0079    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -1.7909   -4.2891    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.0721   -4.1069    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2948   -4.9066    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.0721   -5.9595    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.4242   -5.4432    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.2743   -5.8482    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.0032   -5.4432    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.7220   -5.8482    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.4408   -5.4432    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.4408   -4.6232    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.7220   -4.2081    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.0032   -4.6232    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.2743   -4.2081    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.4242   -4.6232    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.8983   -3.3004    0.0000 H   0  0  0  0  0  0  0  0  0  0  0  0
   -0.9037   -6.7671    0.0000 H   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  2  3  1  0
  4  3  1  0
  4  5  1  0
  6  5  1  0
  6  1  1  0
  6  7  1  0
  7  8  2  0
  8  9  1  0
  9 10  2  0
 10 11  1  0
 11 12  2  0
 12 13  1  0
 13 14  2  0
 14  9  1  0
 14 15  1  0
 15 16  2  0
 16  4  1  0
 16  7  1  0
  4 17  1  1
  6 18  1  1
M  END

Alternative Forms

1. Parent:

   

   ALA1076903

   VARENICLINE

2. Alternative Forms:

   

   ALA1076903

   VARENICLINE TARTRATE
3. 

   ALA1076903

   ---

Molecule Features

Natural Product: Yes

Oral: Yes

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: No

Chirality: Yes

Availability: Yes

Prodrug: No

Calculated Properties

Molecular Weight: 211.27

Molecular Weight (Monoisotopic): 211.1109

AlogP: 1.80

#Rotatable Bonds: ┄

Polar Surface Area: 37.81

Molecular Species: BASE

HBA: 3

HBD: 1

#RO5 Violations: ┄

HBA (Lipinski): 3

HBD (Lipinski): 1

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: ┄

CX Basic pKa: 9.73

CX LogP: 1.01

CX LogD: -1.27

Aromatic Rings: 2

Heavy Atoms: 16

QED Weighted: 0.72

Np Likeness Score: 0.25

References

1. Coe JW, Brooks PR, Wirtz MC, Bashore CG, Bianco KE, Vetelino MG, Arnold EP, Lebel LA, Fox CB, Tingley FD, Schulz DW, Davis TI, Sands SB, Mansbach RS, Rollema H, O'Neill BT..  (2005)  3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation.,  15  (22): [PMID:16171993] [10.1016/j.bmcl.2005.08.035]

2. Ivy Carroll F, Yokota Y, Ma W, Lee JR, Brieaddy LE, Burgess JP, Navarro HA, Damaj MI, Martin BR..  (2008)  Synthesis, nicotinic acetylcholine receptor binding, and pharmacological properties of 3'-(substituted phenyl)deschloroepibatidine analogs.,  16  (2): [PMID:17964169] [10.1016/j.bmc.2007.10.027]

3. Carroll FI, Ma W, Deng L, Navarro HA, Damaj MI, Martin BR..  (2010)  Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3'-(substituted phenyl)epibatidine analogues. Nicotinic partial agonists.,  73  (3): [PMID:20038125] [10.1021/np9006124]

4. Lowe JA, DeNinno SL, Coe JW, Zhang L, Mente S, Hurst RS, Mather RJ, Ward KM, Shrikhande A, Rollema H, Johnson DE, Horner W, Gorczyca R, Tingley FD, Kozak R, Majchrzak MJ, Tritto T, Sadlier J, Shaffer CL, Ellerbrock B, Osgood SM, MacDougall MC, McDowell LL..  (2010)  A novel series of [3.2.1] azabicyclic biaryl ethers as alpha3beta4 and alpha6/4beta4 nicotinic receptor agonists.,  20  (16): [PMID:20663668] [10.1016/j.bmcl.2010.06.142]

5. International Transporter Consortium, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L..  (2010)  Membrane transporters in drug development.,  9  (3): [PMID:20190787] [10.1038/nrd3028]

6. 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]

7. Bolchi C, Gotti C, Binda M, Fumagalli L, Pucci L, Pistillo F, Vistoli G, Valoti E, Pallavicini M..  (2011)  Unichiral 2-(2'-pyrrolidinyl)-1,4-benzodioxanes: the 2R,2'S diastereomer of the N-methyl-7-hydroxy analogue is a potent α4β2- and α6β2-nicotinic acetylcholine receptor partial agonist.,  54  (21): [PMID:21942635] [10.1021/jm200937t]

8. Bréthous L, Garcia-Delgado N, Schwartz J, Bertrand S, Bertrand D, Reymond JL..  (2012)  Synthesis and nicotinic receptor activity of chemical space analogues of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) and 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester (SSR180711).,  55  (10): [PMID:22591063] [10.1021/jm300030r]

9. 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]

10. Ondachi P, Castro A, Luetje CW, Damaj MI, Mascarella SW, Navarro HA, Carroll FI..  (2012)  Synthesis and nicotinic acetylcholine receptor in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues of 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine.,  55  (14): [PMID:22742586] [10.1021/jm300575y]

11. Yu LF, Tückmantel W, Eaton JB, Caldarone B, Fedolak A, Hanania T, Brunner D, Lukas RJ, Kozikowski AP..  (2012)  Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity.,  55  (2): [PMID:22148173] [10.1021/jm201301h]

12. Breining SR, Melvin M, Bhatti BS, Byrd GD, Kiser MN, Hepler CD, Hooker DN, Zhang J, Reynolds LA, Benson LR, Fedorov NB, Sidach SS, Mitchener JP, Lucero LM, Lukas RJ, Whiteaker P, Yohannes D..  (2012)  Structure-activity studies of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes: a novel class of highly potent nicotinic receptor ligands.,  55  (22): [PMID:23025891] [10.1021/jm3011299]

13. Yu LF, Eaton JB, Fedolak A, Zhang HK, Hanania T, Brunner D, Lukas RJ, Kozikowski AP..  (2012)  Discovery of highly potent and selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists containing an isoxazolylpyridine ether scaffold that demonstrate antidepressant-like activity. Part II.,  55  (22): [PMID:23092294] [10.1021/jm301177j]

14. Liu Y, Richardson J, Tran T, Al-Muhtasib N, Xie T, Yenugonda VM, Sexton HG, Rezvani AH, Levin ED, Sahibzada N, Kellar KJ, Brown ML, Xiao Y, Paige M..  (2013)  Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective α4β2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats.,  56  (7): [PMID:23540678] [10.1021/jm4000374]

15. Bagal SK, Brown AD, Cox PJ, Omoto K, Owen RM, Pryde DC, Sidders B, Skerratt SE, Stevens EB, Storer RI, Swain NA..  (2013)  Ion channels as therapeutic targets: a drug discovery perspective.,  56  (3): [PMID:23121096] [10.1021/jm3011433]

16. Yenugonda VM, Xiao Y, Levin ED, Rezvani AH, Tran T, Al-Muhtasib N, Sahibzada N, Xie T, Wells C, Slade S, Johnson JE, Dakshanamurthy S, Kong HS, Tomita Y, Liu Y, Paige M, Kellar KJ, Brown ML..  (2013)  Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands.,  56  (21): [PMID:24047231] [10.1021/jm4008455]

17. Ondachi PW, Castro AH, Bartkowiak JM, Luetje CW, Damaj MI, Mascarella SW, Navarro HA, Carroll FI..  (2014)  Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2'-fluoro-3'-(substituted pyridinyl)-7-deschloroepibatidine analogues.,  57  (3): [PMID:24428686] [10.1021/jm401602p]

18. PubChem BioAssay data set, 

19. Onajole OK, Eaton JB, Lukas RJ, Brunner D, Thiede L, Caldarone BJ, Kozikowski AP..  (2014)  Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective α4β2-nAChR Ligands.,  5  (11): [PMID:25408831] [10.1021/ml500129k]

20. Yu LF, Zhang HK, Caldarone BJ, Eaton JB, Lukas RJ, Kozikowski AP..  (2014)  Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.,  57  (20): [PMID:24901260] [10.1021/jm401937a]

21. Ondachi PW, Ye Z, Castro AH, Luetje CW, Damaj MI, Mascarella SW, Navarro HA, Carroll FI..  (2015)  Synthesis, nicotinic acetylcholine receptor binding, in vitro and in vivo pharmacology properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs.,  23  (17): [PMID:26233800] [10.1016/j.bmc.2015.07.021]

22. WHO Anatomical Therapeutic Chemical Classification, 

23.  (2016)  Nicotinic receptor compounds, 

24.  (2016)  2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof, 

25. 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]

26. Unpublished dataset, 

27. 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]

28. 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]

29. Nirogi R, Mohammed AR, Shinde AK, Ravella SR, Bogaraju N, Subramanian R, Mekala VR, Palacharla RC, Muddana N, Thentu JB, Bhyrapuneni G, Abraham R, Jasti V..  (2020)  Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression.,  63  (6): [PMID:32026697] [10.1021/acs.jmedchem.9b00790]

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

Source

Source(7):

• Scientific Literature
• PubChem BioAssays
• Clinical Candidates
• BindingDB Database
• WHO Anatomical Therapeutic Chemical Classification
• SARS-CoV-2 Screening Data 2020-21
• IMI-CARE SARS-CoV-2 Data