7-Fluoro-2-(4-methyl-3-oxopiperazin-1-yl)-3-(4-(trifluoromethoxy)-phenyl)-quinazolin-4(3H)-one

ID: ALA4537519

PubChem CID: 155548588

Max Phase: Preclinical

Molecular Formula: C20H16F4N4O2

Molecular Weight: 420.37

Molecule Type: Unknown

Names and Identifiers

Canonical SMILES:  CN1CCN(c2nc3cc(F)ccc3c(=O)n2-c2ccc(C(F)(F)F)cc2)CC1=O

Standard InChI:  InChI=1S/C20H16F4N4O2/c1-26-8-9-27(11-17(26)29)19-25-16-10-13(21)4-7-15(16)18(30)28(19)14-5-2-12(3-6-14)20(22,23)24/h2-7,10H,8-9,11H2,1H3

Standard InChI Key:  NPZBKVRAQCZVDA-UHFFFAOYSA-N

Molfile:  

 
     RDKit          2D

 30 33  0  0  0  0  0  0  0  0999 V2000
   27.8175   -4.3006    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   22.8552   -3.0789    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   22.8540   -3.8984    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   23.5621   -4.3074    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   23.5603   -2.6700    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   24.2689   -3.0753    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   24.2723   -3.9005    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   24.9847   -4.3079    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   25.6982   -3.8946    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   25.6948   -3.0694    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   24.9779   -2.6575    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   24.9734   -1.8403    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   26.4002   -2.6590    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.1095   -3.0671    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.8155   -2.6570    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.8134   -1.8389    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.0994   -1.4327    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   26.3964   -1.8451    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   26.4070   -4.3013    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   22.1460   -4.3064    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   26.4062   -5.1232    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.1109   -5.5298    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.8199   -5.1227    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   27.1104   -3.8935    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   28.5272   -5.5321    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   28.5184   -1.4276    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   29.1607   -1.0529    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   29.3180   -1.7275    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   28.6510   -0.5839    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   28.5244   -3.8905    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
  2  3  2  0
  3  4  1  0
  4  7  2  0
  6  5  2  0
  5  2  1  0
  6  7  1  0
  6 11  1  0
  7  8  1  0
  8  9  2  0
  9 10  1  0
 10 11  1  0
 11 12  2  0
 13 14  2  0
 14 15  1  0
 15 16  2  0
 16 17  1  0
 17 18  2  0
 18 13  1  0
 10 13  1  0
  9 19  1  0
  3 20  1  0
 19 21  1  0
 19 24  1  0
 21 22  1  0
 22 23  1  0
 23  1  1  0
 23 25  1  0
 24  1  1  0
 26 27  1  0
 26 28  1  0
 26 29  1  0
 16 26  1  0
  1 30  2  0
M  END

Alternative Forms

1. Parent:

   

   ALA4537519

   ---

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: 420.37

Molecular Weight (Monoisotopic): 420.1209

AlogP: 2.82

#Rotatable Bonds: 2

Polar Surface Area: 58.44

Molecular Species: NEUTRAL

HBA: 5

HBD: ┄

#RO5 Violations: ┄

HBA (Lipinski): 6

HBD (Lipinski): ┄

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: ┄

CX Basic pKa: 4.18

CX LogP: 2.89

CX LogD: 2.89

Aromatic Rings: 3

Heavy Atoms: 30

QED Weighted: 0.60

Np Likeness Score: -1.49

References

1. Atobe M, Nagami T, Muramatsu S, Ohno T, Kitagawa M, Suzuki H, Ishiguro M, Watanabe A, Kawanishi M..  (2019)  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.,  62  (3): [PMID:30629441] [10.1021/acs.jmedchem.8b01615]

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