(2R,3R)-1-[4-(2-Chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide

ID: ALA187092

PubChem CID: 44395506

Max Phase: Preclinical

Molecular Formula: C20H22ClFN2O6S

Molecular Weight: 472.92

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  C[C@@]1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3Cl)cc2)[C@H]1C(=O)NO

Standard InChI:  InChI=1S/C20H22ClFN2O6S/c1-20(26)9-2-10-24(18(20)19(25)23-27)31(28,29)16-7-5-15(6-8-16)30-12-13-3-4-14(22)11-17(13)21/h3-8,11,18,26-27H,2,9-10,12H2,1H3,(H,23,25)/t18-,20+/m0/s1

Standard InChI Key:  LTVIJEFEZVFIST-AZUAARDMSA-N

Molfile:  

     RDKit          2D

 31 33  0  0  1  0  0  0  0  0999 V2000
   -0.5500   -0.6000    0.0000 S   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5500    0.2250    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.1625    0.6333    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8750    0.2208    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5583   -1.4250    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1625    1.4583    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.2750   -0.6000    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -1.3750   -0.5917    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    1.5542   -4.3042    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8417   -3.8917    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.2667   -3.8917    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2792   -0.4917    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    1.5875    0.6375    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.1292   -4.3042    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8375   -3.0667    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2583    0.6333    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2750   -1.8250    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1500   -1.8375    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5833   -3.8917    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    2.2667   -3.0667    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.5542   -5.1292    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
   -0.5750   -3.0667    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1542    2.2833    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    1.5500   -2.6542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2833   -2.6500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1417   -2.6625    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.9792   -2.6542    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    2.3000    0.2250    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5500    1.8750    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2583    1.4583    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.9542    1.6750    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  2  1  1  0
  3  2  1  0
  3  4  1  6
  5  1  1  0
  6  3  1  0
  7  1  2  0
  8  1  2  0
  9 10  2  0
 10 14  1  0
 11  9  1  0
 12  4  2  0
 13  4  1  0
 14 19  1  0
 15 10  1  0
 16  2  1  0
 17  5  2  0
 18  5  1  0
 19 22  1  0
 20 24  1  0
 21  9  1  0
 22 26  1  0
  6 23  1  1
 24 15  2  0
 25 17  1  0
 26 18  2  0
 27 20  1  0
 28 13  1  0
 29 30  1  0
 30 16  1  0
  6 31  1  6
 22 25  2  0
 29  6  1  0
 20 11  2  0
M  END

Alternative Forms

1. Parent:

   

   ALA187092

   (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 472.92

Molecular Weight (Monoisotopic): 472.0871

AlogP: 2.47

#Rotatable Bonds: 6

Polar Surface Area: 116.17

Molecular Species: NEUTRAL

HBA: 6

HBD: 3

#RO5 Violations: ┄

HBA (Lipinski): 8

HBD (Lipinski): 3

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 8.68

CX Basic pKa: ┄

CX LogP: 2.28

CX LogD: 2.25

Aromatic Rings: 2

Heavy Atoms: 31

QED Weighted: 0.44

Np Likeness Score: -1.14

References

1. Noe MC, Natarajan V, Snow SL, Wolf-Gouveia LA, Mitchell PG, Lopresti-Morrow L, Reeves LM, Yocum SA, Otterness I, Bliven MA, Carty TJ, Barberia JT, Sweeney FJ, Liras JL, Vaughn M..  (2005)  Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.,  15  (14): [PMID:15953722] [10.1016/j.bmcl.2005.05.037]

2. Deng H, O'Keefe H, Davie CP, Lind KE, Acharya RA, Franklin GJ, Larkin J, Matico R, Neeb M, Thompson MM, Lohr T, Gross JW, Centrella PA, O'Donovan GK, Bedard KL, van Vloten K, Mataruse S, Skinner SR, Belyanskaya SL, Carpenter TY, Shearer TW, Clark MA, Cuozzo JW, Arico-Muendel CC, Morgan BA..  (2012)  Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT).,  55  (16): [PMID:22891645] [10.1021/jm300449x]

3. Durham TB, Klimkowski VJ, Rito CJ, Marimuthu J, Toth JL, Liu C, Durbin JD, Stout SL, Adams L, Swearingen C, Lin C, Chambers MG, Thirunavukkarasu K, Wiley MR..  (2014)  Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis.,  57  (24): [PMID:25415648] [10.1021/jm501522n]

4.  (2001)  Selective inhibitors of aggrecanase in osteoarthritis treatment, 

5. Durham TB, Marimuthu J, Toth JL, Liu C, Adams L, Mudra DR, Swearingen C, Lin C, Chambers MG, Thirunavukkarasu K, Wiley MR..  (2017)  A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose.,  60  (13): [PMID:28613895] [10.1021/acs.jmedchem.7b00650]

6. Wiley MR, Durham TB, Adams LA, Chambers MG, Lin C, Liu C, Marimuthu J, Mitchell PG, Mudra DR, Swearingen CA, Toth JL, Weller JM, Thirunavukkarasu K..  (2016)  Use of Osmotic Pumps to Establish the Pharmacokinetic-Pharmacodynamic Relationship and Define Desirable Human Performance Characteristics for Aggrecanase Inhibitors.,  59  (12): [PMID:27194201] [10.1021/acs.jmedchem.6b00398]

Source

Source(2):

• Scientific Literature
• Patent Bioactivity Data