1-tert-Butyl-N-[4-cyclobutyl-5-(4-methylpiperazin-1-yl)-1,3-thiazol-2-yl]-5-methyl-1H-pyrazole-4-carboxamide hydrogen chloride

ID: ALA4519974

PubChem CID: 155542105

Max Phase: Preclinical

Molecular Formula: C21H33ClN6OS

Molecular Weight: 416.60

Molecule Type: Unknown

Names and Identifiers

Canonical SMILES:  Cc1c(C(=O)Nc2nc(C3CCC3)c(N3CCN(C)CC3)s2)cnn1C(C)(C)C.Cl

Standard InChI:  InChI=1S/C21H32N6OS.ClH/c1-14-16(13-22-27(14)21(2,3)4)18(28)24-20-23-17(15-7-6-8-15)19(29-20)26-11-9-25(5)10-12-26;/h13,15H,6-12H2,1-5H3,(H,23,24,28);1H

Standard InChI Key:  JRRXSWGENQXETD-UHFFFAOYSA-N

Molfile:  

     RDKit          2D

 30 32  0  0  0  0  0  0  0  0999 V2000
   10.3263   -7.0823    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
    7.3671   -4.4739    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.4061   -5.1948    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.5890   -5.1896    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.1849   -4.4793    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    8.1759   -5.8947    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    6.8907   -3.8092    0.0000 S   0  0  0  0  0  0  0  0  0  0  0  0
    6.1113   -4.0568    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.1059   -4.8747    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.8820   -5.1324    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.3984   -3.6443    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.4012   -2.8198    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.6924   -2.4075    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.9764   -2.8151    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    3.9736   -3.6396    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.6869   -4.0565    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.2706   -2.4032    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.3943   -5.2787    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.6054   -5.0613    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.3880   -5.8501    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.1769   -6.0676    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.8809   -5.8597    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.6597   -5.6121    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   10.6649   -4.7948    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    9.8893   -4.5375    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.3290   -4.3187    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.6413   -3.7588    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.0734   -4.6557    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.2487   -3.5054    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.0309   -3.9044    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  3  4  1  0
  4  5  1  0
  4  6  2  0
  5  2  1  0
  2  7  1  0
  7  8  1  0
  8  9  2  0
  9 10  1  0
 10  2  2  0
  8 11  1  0
 11 12  1  0
 11 16  1  0
 12 13  1  0
 13 14  1  0
 14 15  1  0
 15 16  1  0
 14 17  1  0
  9 18  1  0
 18 19  1  0
 19 20  1  0
 20 21  1  0
 21 18  1  0
  3 22  1  0
 22 23  2  0
 23 24  1  0
 24 25  1  0
 25  3  2  0
 24 26  1  0
 25 27  1  0
 26 28  1  0
 26 29  1  0
 26 30  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: 416.60

Molecular Weight (Monoisotopic): 416.2358

AlogP: 3.67

#Rotatable Bonds: 4

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: 11.17

CX Basic pKa: 6.99

CX LogP: 3.57

CX LogD: 3.42

Aromatic Rings: 2

Heavy Atoms: 29

QED Weighted: 0.82

Np Likeness Score: -1.76

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