N-[4-Cyclobutyl-5-(4-methylpiperazin-1-yl)-1,3-thiazol-2-yl]-1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazole-4-carboxamide dihydrochloride

ID: ALA4531567

PubChem CID: 155546455

Max Phase: Preclinical

Molecular Formula: C23H34Cl2F2N6OS

Molecular Weight: 478.61

Molecule Type: Unknown

Names and Identifiers

Canonical SMILES:  Cc1c(C(=O)Nc2nc(C3CCC3)c(N3CCN(C)CC3)s2)cnn1C1CCC(F)(F)CC1.Cl.Cl

Standard InChI:  InChI=1S/C23H32F2N6OS.2ClH/c1-15-18(14-26-31(15)17-6-8-23(24,25)9-7-17)20(32)28-22-27-19(16-4-3-5-16)21(33-22)30-12-10-29(2)11-13-30;;/h14,16-17H,3-13H2,1-2H3,(H,27,28,32);2*1H

Standard InChI Key:  FDPJLHBRTJFRRM-UHFFFAOYSA-N

Molfile:  

     RDKit          2D

 35 37  0  0  0  0  0  0  0  0999 V2000
   11.1600  -13.4837    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
   13.1824   -9.1790    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   12.7779   -9.8888    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.5949   -9.8842    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    7.4909  -10.9908    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.5300  -11.7117    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.7128  -11.7065    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.3087  -10.9962    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    8.2997  -12.4116    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    7.0145  -10.3261    0.0000 S   0  0  0  0  0  0  0  0  0  0  0  0
    6.2351  -10.5737    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.2297  -11.3915    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.0058  -11.6493    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.5222  -10.1612    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.5250   -9.3367    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.8162   -8.9244    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.1002   -9.3320    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.0975  -10.1565    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.8107  -10.5734    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.3944   -8.9201    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.5181  -11.7956    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.7293  -11.5781    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5118  -12.3670    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.3007  -12.5845    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.0047  -12.3765    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.7835  -12.1290    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   10.7887  -11.3117    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   10.0131  -11.0544    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.4528  -10.8356    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.7652  -10.2757    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.1940  -11.1780    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.8563  -10.7054    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.0357   -9.5522    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.3673  -10.0270    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.6878   -9.0634    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
  3  2  1  0
  4  3  1  0
  6  7  1  0
  7  8  1  0
  7  9  2  0
  8  5  1  0
  5 10  1  0
 10 11  1  0
 11 12  2  0
 12 13  1  0
 13  5  2  0
 11 14  1  0
 14 15  1  0
 14 19  1  0
 15 16  1  0
 16 17  1  0
 17 18  1  0
 18 19  1  0
 17 20  1  0
 12 21  1  0
 21 22  1  0
 22 23  1  0
 23 24  1  0
 24 21  1  0
  6 25  1  0
 25 26  2  0
 26 27  1  0
 27 28  1  0
 28  6  2  0
 27 29  1  0
 28 30  1  0
 29 31  1  0
 29 34  1  0
 31 32  1  0
 32  3  1  0
  3 33  1  0
 33 34  1  0
M  END

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: 478.61

Molecular Weight (Monoisotopic): 478.2326

AlogP: 4.67

#Rotatable Bonds: 5

Polar Surface Area: 66.29

Molecular Species: NEUTRAL

HBA: 7

HBD: 1

#RO5 Violations: ┄

HBA (Lipinski): 7

HBD (Lipinski): 1

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 11.18

CX Basic pKa: 6.99

CX LogP: 3.80

CX LogD: 3.66

Aromatic Rings: 2

Heavy Atoms: 33

QED Weighted: 0.68

Np Likeness Score: -1.53

References

1. Sami Y, Morita M, Kubota H, Hirabayashi R, Seo R, Nakagawa N..  (2019)  Discovery of a novel orally active TRPV4 inhibitor: Part 1. Optimization from an HTS hit.,  27  (17): [PMID:31327678] [10.1016/j.bmc.2019.05.041]

2. Watanabe, Hiroyuki H and 13 more authors.  2002-04-19  Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives.  [PMID:11827975]

3. Suzuki, Makoto M, Mizuno, Atsuko A, Kodaira, Kunihiko K and Imai, Masashi M.  2003-06-20  Impaired pressure sensation in mice lacking TRPV4.  [PMID:12692122]

4. Xu, Feng F, Satoh, Eisaku E and Iijima, Toshihiko T.  2003-09  Protein kinase C-mediated Ca2+ entry in HEK 293 cells transiently expressing human TRPV4.  [PMID:12970074]

5. Everaerts, Wouter W and 17 more authors.  2010-11-02  Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis.  [PMID:20956320]

6. Thorneloe, Kevin S KS and 35 more authors.  2012-11-07  An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure.  [PMID:23136043]

7. Washburn, David G DG and 22 more authors.  2013-09-01  The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore.  [PMID:23886683]

8. Hilfiker, Mark A MA and 8 more authors.  2013-02-14  Optimization of a Novel Series of TRPV4 Antagonists with In Vivo Activity in a Model of Pulmonary Edema.  [PMID:24900661]

9. Cheung, Mui M and 15 more authors.  2017-05-11  Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4.  [PMID:28523109]

10. Brnardic, Edward J EJ and 17 more authors.  2018-11-08  Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4).  [PMID:30335378]

11. Pero, Joseph E JE and 27 more authors.  2018-12-27  Design and Optimization of Sulfone Pyrrolidine Sulfonamide Antagonists of Transient Receptor Potential Vanilloid-4 with in Vivo Activity in a Pulmonary Edema Model.  [PMID:30500190]

12. Atobe, Masakazu M and 8 more authors.  2019-02-14  Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3 H)-ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis.  [PMID:30629441]

13. Sami, Yuichi Y and 5 more authors.  2019-09-01  Discovery of a novel orally active TRPV4 inhibitor: Part 1. Optimization from an HTS hit.  [PMID:31327678]

14. Brooks, Carl A CA and 17 more authors.  2019-08-08  Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4).  [PMID:31413810]

15. Lawhorn, Brian G; Brnardic, Edward J and Behm, David J.  2020-04-15  Recent advances in TRPV4 agonists and antagonists.  [PMID:32063431]

16. Liu, Na; Yan, Fang; Ma, Qingjie and Zhao, Jianhua.  2020-08-15  Modulation of TRPV4 and BKCa for treatment of brain diseases.  [PMID:32690264]

17. Patterson, Jaclyn R and 11 more authors.  2020-12-10  Design and Optimization of an Acyclic Amine Series of TRPV4 Antagonists by Electronic Modulation of Hydrogen Bond Interactions.  [PMID:33201708]

Source

Source(1):

• Scientific Literature