(2S,4R)-N-((S)-3-(4-((4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)ethynyl)-1,4'-bipiperidin-1'-ylamino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide

ID: ALA4743244

PubChem CID: 162647195

Max Phase: Preclinical

Molecular Formula: C58H62F3N11O6S2

Molecular Weight: 1130.33

Molecule Type: Unknown

Names and Identifiers

Canonical SMILES:  Cc1cc([C@H](C(=O)N2C[C@H](O)C[C@H]2C(=O)N[C@@H](CC(=O)NN2CCC(N3CCC(C#Cc4ccc(N5C(=S)N(c6cnc(C#N)c(C(F)(F)F)c6)C(=O)C56CCC6)cc4)CC3)CC2)c2ccc(-c3scnc3C)cc2)C(C)C)on1

Standard InChI:  InChI=1S/C58H62F3N11O6S2/c1-34(2)51(49-26-35(3)67-78-49)54(76)70-32-44(73)28-48(70)53(75)65-46(39-10-12-40(13-11-39)52-36(4)64-33-80-52)29-50(74)66-69-24-18-41(19-25-69)68-22-16-38(17-23-68)7-6-37-8-14-42(15-9-37)72-56(79)71(55(77)57(72)20-5-21-57)43-27-45(58(59,60)61)47(30-62)63-31-43/h8-15,26-27,31,33-34,38,41,44,46,48,51,73H,5,16-25,28-29,32H2,1-4H3,(H,65,75)(H,66,74)/t44-,46+,48+,51-/m1/s1

Standard InChI Key:  AUCRIPCZHFOUTM-YUWVYYDQSA-N

Molfile:  

 
     RDKit          2D

 80 89  0  0  0  0  0  0  0  0999 V2000
    5.1539  -18.1076    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.9393  -18.8959    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.7276  -19.1105    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9422  -18.3222    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.0319  -14.4373    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    2.8285  -14.6561    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.6181  -13.8584    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    2.1254  -15.8901    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.1243  -16.7137    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.8364  -17.1268    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.5502  -16.7133    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.5474  -15.8865    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.8346  -15.4812    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.2632  -17.1225    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.3499  -17.9392    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.5612  -17.3953    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.0092  -16.7848    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.1819  -15.9811    0.0000 S   0  0  0  0  0  0  0  0  0  0  0  0
    1.4135  -15.4817    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.5428  -14.2451    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    3.7394  -18.4869    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.6982  -15.0673    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    7.6144  -18.0848    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.0190  -17.3729    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.6084  -16.6666    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7893  -16.6710    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.3825  -17.3875    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7995  -18.0909    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.8360  -17.3673    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.6573  -17.3632    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.4786  -17.3592    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.8900  -18.0728    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.7078  -18.0708    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.1167  -17.3587    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   11.7059  -16.6471    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.8819  -16.6475    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.9334  -17.3569    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.3457  -18.0701    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.1634  -18.0712    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.5751  -17.3607    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   14.1669  -16.6475    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.3430  -16.6448    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.3926  -17.3603    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   15.8050  -16.6483    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6263  -16.6479    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.0346  -15.9358    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.3920  -15.9366    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   17.8559  -15.9355    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.2657  -16.6500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.0863  -16.6499    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.4953  -15.9374    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.0820  -15.2234    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.2628  -15.2269    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6257  -15.2242    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   17.0339  -14.5122    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6250  -13.8047    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.9536  -13.0530    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   16.3419  -12.5023    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.6384  -12.9154    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.8047  -13.7187    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.7566  -12.8768    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.3091  -13.4868    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   18.0071  -12.0990    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.8101  -11.9229    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.4587  -11.4890    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.7091  -10.7070    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6556  -11.6610    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.4235  -12.4677    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.1343  -12.0531    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.9623  -11.2459    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   19.1452  -11.1669    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   20.8858  -12.3876    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.3156  -15.9333    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.8013  -16.5976    0.0000 S   0  0  0  0  0  0  0  0  0  0  0  0
   21.5822  -16.3437    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   21.5807  -15.5223    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   20.7989  -15.2672    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.5491  -14.4864    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.8553  -14.5118    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   14.8916  -12.5838    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  2  3  1  0
  3  4  1  0
  4  1  1  0
  6  5  1  0
  7  6  1  0
  8  9  2  0
  9 10  1  0
 10 11  2  0
 11 12  1  0
 12 13  2  0
 13  8  1  0
 14 15  1  0
 15  1  1  0
  1 16  1  0
 16 17  1  0
 17 14  1  0
 11 14  1  0
 17 18  2  0
  8 19  1  0
 13  6  1  0
  6 20  1  0
 15 21  2  0
 19 22  3  0
 23 24  2  0
 24 25  1  0
 25 26  2  0
 26 27  1  0
 27 28  2  0
 28 23  1  0
 29 30  3  0
 24 29  1  0
 30 31  1  0
 31 32  1  0
 31 36  1  0
 32 33  1  0
 33 34  1  0
 34 35  1  0
 35 36  1  0
 37 38  1  0
 37 42  1  0
 38 39  1  0
 39 40  1  0
 40 41  1  0
 41 42  1  0
 34 37  1  0
 40 43  1  0
 27 16  1  0
 43 44  1  0
 44 45  1  0
 46 45  1  6
 44 47  2  0
 46 48  1  0
 48 49  2  0
 49 50  1  0
 50 51  2  0
 51 52  1  0
 52 53  2  0
 53 48  1  0
 46 54  1  0
 54 55  1  0
 56 55  1  6
 56 57  1  0
 57 58  1  0
 58 59  1  0
 59 60  1  0
 60 56  1  0
 57 61  1  0
 61 62  2  0
 61 63  1  0
 63 64  1  6
 63 65  1  0
 65 66  1  0
 65 67  1  0
 64 68  2  0
 68 69  1  0
 69 70  2  0
 70 71  1  0
 71 64  1  0
 69 72  1  0
 73 74  1  0
 74 75  1  0
 75 76  2  0
 76 77  1  0
 77 73  2  0
 51 73  1  0
 77 78  1  0
 55 79  2  0
 59 80  1  1
M  END

Alternative Forms

1. Parent:

   

   ALA4743244

   ---

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Unknown

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 1130.33

Molecular Weight (Monoisotopic): 1129.4278

AlogP: ┄

#Rotatable Bonds: ┄

Polar Surface Area: ┄

Molecular Species: ┄

HBA: ┄

HBD: ┄

#RO5 Violations: ┄

HBA (Lipinski): ┄

HBD (Lipinski): ┄

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: ┄

CX Basic pKa: ┄

CX LogP: ┄

CX LogD: ┄

Aromatic Rings: ┄

Heavy Atoms: ┄

QED Weighted: ┄

Np Likeness Score: ┄

References

1. Kargbo RB.  (2021)  Androgen Receptor Protein Degradation in the Treatment of Castration-Resistant Prostate Cancer.,  12  (3): [PMID:33738051] [10.1021/acsmedchemlett.1c00059]

2. Tilley, W D WD, Marcelli, M M, Wilson, J D JD and McPhaul, M J MJ.  1989-01  Characterization and expression of a cDNA encoding the human androgen receptor.  [PMID:2911578]

3. Hamann, L G LG and 8 more authors.  1998-02-12  Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines.  [PMID:9484511]

4. Wang, L G LG, Liu, X M XM, Kreis, W W and Budman, D R DR.  1998-05-01  Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor.  [PMID:10076535]

5. Giwercman, A A and 7 more authors.  2000-06  Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene.  [PMID:10852459]

6. Fuhrmann, U U and 7 more authors.  2000-12-28  Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist.  [PMID:11150172]

7. Handratta, Venkatesh D VD and 10 more authors.  2005-04-21  Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model.  [PMID:15828836]

8. Kinoyama, Isao I and 16 more authors.  2006-01-26  (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.  [PMID:16420057]

9. Larsson, Anders A, Eriksson, Leif A LA, Andersson, Patrik L PL, Ivarson, Per P and Olsson, Per-Erik PE.  2006-12-14  Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist.  [PMID:17149866]

10. van Oeveren, Arjan A and 11 more authors.  2007-03-15  Novel selective androgen receptor modulators: SAR studies on 6-bisalkylamino-2-quinolinones.  [PMID:17267219]

11. Fensome, Andrew A and 19 more authors.  2008-03-27  Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348).  [PMID:18318463]

12. Li, Jie Jack JJ and 23 more authors.  2008-11-13  Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen receptor antagonist devoid of phototoxicity for dermatological indications.  [PMID:18921992]

13. Tran, Chris C and 18 more authors.  2009-05-08  Development of a second-generation antiandrogen for treatment of advanced prostate cancer.  [PMID:19359544]

14. Schlienger, Nathalie N and 12 more authors.  2009-11-26  Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.  [PMID:19856921]

15. Jung, Michael E and 6 more authors.  2010-04-08  Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC).  [PMID:20218717]

16. Zhou, Hai-Bing HB, Lee, Jae Hak JH, Mayne, Christopher G CG, Carlson, Kathryn E KE and Katzenellenbogen, John A JA.  2010-04-22  Imaging progesterone receptor in breast tumors: synthesis and receptor binding affinity of fluoroalkyl-substituted analogues of tanaproget.  [PMID:20355713]

17. Arhancet, Graciela B and 14 more authors.  2010-08-26  Discovery of novel cyanodihydropyridines as potent mineralocorticoid receptor antagonists.  [PMID:20672820]

18. Yoshino, Hitoshi H and 16 more authors.  2010-12-01  Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.  [PMID:21050768]

19. Guo, Chuangxing C and 28 more authors.  2011-11-10  Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists.  [PMID:21936524]

20. Hasui, Tomoaki and 18 more authors.  2011-12-22  Identification of benzoxazin-3-one derivatives as novel, potent, and selective nonsteroidal mineralocorticoid receptor antagonists.  [PMID:22074142]

21. Yamamoto, Satoshi S and 13 more authors.  2012-01-01  Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.  [PMID:22094279]

22. Guo, Chuangxing C and 11 more authors.  2012-01-15  Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer.  [PMID:22197140]

23. Yamamoto, Satoshi S and 10 more authors.  2012-04-01  Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.  [PMID:22391033]

24. Poutiainen, Pekka K PK and 6 more authors.  2012-07-26  Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators.  [PMID:22746350]

25. Yamamoto, Satoshi S and 9 more authors.  2013-01-01  Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.  [PMID:23199477]

26. Liedtke, Andy J AJ and 7 more authors.  2013-03-28  Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.  [PMID:23432095]

27. Purushottamachar, Puranik P and 8 more authors.  2013-06-27  Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.  [PMID:23713567]

28. Maruyama, Keisuke K and 6 more authors.  2013-07-15  Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ERα-selective antagonist.  [PMID:23768907]

29. Akita, Kazumasa K and 5 more authors.  2013-11-15  A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate.  [PMID:24177288]

30. Richardson, Timothy I TI and 18 more authors.  2011-02-10  Novel 3-aryl indoles as progesterone receptor antagonists for uterine fibroids.  [PMID:24900294]

31. Li, Huifang H and 8 more authors.  2014-08-14  Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor.  [PMID:25062331]

32. Ullrich, Thomas T and 21 more authors.  2014-09-11  3-alkoxy-pyrrolo[1,2-b]pyrazolines as selective androgen receptor modulators with ideal physicochemical properties for transdermal administration.  [PMID:25121964]

33. Gege, Christian C, Schlüter, Thomas T and Hoffmann, Thomas T.  2014-11-15  Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt.  [PMID:25305688]

34. Sundén, Henrik H and 6 more authors.  2015-02-12  Synthesis and biological evaluation of second-generation tropanol-based androgen receptor modulators.  [PMID:25646649]

35. Aikawa, Katsuji K and 11 more authors.  2015-05-15  Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part I.  [PMID:25862209]

36. Jadhavar, Pradeep S PS and 20 more authors.  2016-11-01  Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors.  [PMID:27717544]

37. Shibata, Norihito N and 11 more authors.  2018-01-25  Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands.  [PMID:28594553]

38. Unwalla, Ray R and 18 more authors.  2017-07-27  Structure-Based Approach To Identify 5-[4-Hydroxyphenyl]pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators.  [PMID:28696695]

39. Nishiyama, Yuko Y and 6 more authors.  2018-07-12  Novel Nonsteroidal Progesterone Receptor (PR) Antagonists with a Phenanthridinone Skeleton.  [PMID:30034593]

40. Rew, Yosup Y and 19 more authors.  2018-09-13  Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).  [PMID:30091920]

41. Dalal, Kush K and 11 more authors.  2018-09-05  Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor.  [PMID:30193215]

42. Hwang, Dong-Jin DJ and 7 more authors.  2019-01-24  New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity.  [PMID:30525603]

43. Yu, Jiang J and 7 more authors.  2019-06-01  Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer.  [PMID:30925341]

44. Du, Xiaohui X and 16 more authors.  2019-07-25  Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633).  [PMID:31274313]

45. Tang, Qin and 12 more authors.  2020-04-15  Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and biological evaluation.  [PMID:32114360]

46. He, Yali and 6 more authors.  2020-11-12  Pyrazol-1-yl-propanamides as SARD and Pan-Antagonists for the Treatment of Enzalutamide-Resistant Prostate Cancer.  [PMID:33095584]

47. Wang, Ao; Wang, Yawan; Meng, Xin and Yang, Yushe.  2021-02-01  Design, synthesis and biological evaluation of novel thiohydantoin derivatives as potent androgen receptor antagonists for the treatment of prostate cancer.  [PMID:33388655]

48. Zhang, Zhuming and 17 more authors.  2021-01-28  Discovery of JNJ-63576253: A Clinical Stage Androgen Receptor Antagonist for F877L Mutant and Wild-Type Castration-Resistant Prostate Cancer (mCRPC).  [PMID:33470111]

Source

Source(1):

• Scientific Literature