(2S,4R)-1-((S)-2-Acetamido-3,3-dimethyl butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

ID: ALA3344081

Chembl Id: CHEMBL3344081

Cas Number: 1448188-62-2

PubChem CID: 77232228

Max Phase: Preclinical

Molecular Formula: C24H32N4O4S

Molecular Weight: 472.61

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  CC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)NCc1ccc(-c2scnc2C)cc1)C(C)(C)C

Standard InChI:  InChI=1S/C24H32N4O4S/c1-14-20(33-13-26-14)17-8-6-16(7-9-17)11-25-22(31)19-10-18(30)12-28(19)23(32)21(24(3,4)5)27-15(2)29/h6-9,13,18-19,21,30H,10-12H2,1-5H3,(H,25,31)(H,27,29)/t18-,19+,21-/m1/s1

Standard InChI Key:  GFVIEZBZIUKYOG-SVFBPWRDSA-N

Alternative Forms

1. Parent:

   

   ALA3344081

   N-Acetyl-3-Methyl-L-Valyl-(4r)-4-Hydroxy-N-[4-(4-Methyl-1,3-Thiazol-5-Yl)benzyl]-L-Prolinamide

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: 472.61

Molecular Weight (Monoisotopic): 472.2144

AlogP: 2.25

#Rotatable Bonds: 6

Polar Surface Area: 111.63

Molecular Species: NEUTRAL

HBA: 6

HBD: 3

#RO5 Violations: ┄

HBA (Lipinski): 8

HBD (Lipinski): 3

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 12.60

CX Basic pKa: 2.65

CX LogP: 0.67

CX LogD: 0.67

Aromatic Rings: 2

Heavy Atoms: 33

QED Weighted: 0.60

Np Likeness Score: -0.51

References

1. Galdeano C, Gadd MS, Soares P, Scaffidi S, Van Molle I, Birced I, Hewitt S, Dias DM, Ciulli A..  (2014)  Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities.,  57  (20): [PMID:25166285] [10.1021/jm5011258]

2. Crew AP, Raina K, Dong H, Qian Y, Wang J, Vigil D, Serebrenik YV, Hamman BD, Morgan A, Ferraro C, Siu K, Neklesa TK, Winkler JD, Coleman KG, Crews CM..  (2018)  Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1.,  61  (2): [PMID:28692295] [10.1021/acs.jmedchem.7b00635]

3. Soares P, Gadd MS, Frost J, Galdeano C, Ellis L, Epemolu O, Rocha S, Read KD, Ciulli A..  (2018)  Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).,  61  (2): [PMID:28853884] [10.1021/acs.jmedchem.7b00675]

4. Hu J, Hu B, Wang M, Xu F, Miao B, Yang CY, Wang M, Liu Z, Hayes DF, Chinnaswamy K, Delproposto J, Stuckey J, Wang S..  (2019)  Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER).,  62  (3): [PMID:30990042] [10.1021/acs.jmedchem.8b01572]

5. Blaquiere N, Villemure E, Staben ST..  (2020)  Medicinal Chemistry of Inhibiting RING-Type E3 Ubiquitin Ligases.,  63  (15): [PMID:32142281] [10.1021/acs.jmedchem.9b01451]

6. Klein VG, Bond AG, Craigon C, Lokey RS, Ciulli A..  (2021)  Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity.,  64  (24.0): [PMID:34881891] [10.1021/acs.jmedchem.1c01496]

7. Xue X, Kang JB, Yang X, Li N, Chang L, Ji J, Meng XK, Zhang HQ, Zhong Y, Yu SP, Wu WY, Wang XL, Li NG, Sun SL..  (2022)  An efficient strategy for digging protein-protein interactions for rational drug design - A case study with HIF-1α/VHL.,  227  [PMID:34638033] [10.1016/j.ejmech.2021.113871]

8. Palacios DS..  (2022)  Drug Hunting at the Nexus of Medicinal Chemistry and Chemical Biology and the Discovery of Novel Therapeutic Modalities.,  65  (20.0): [PMID:36206538] [10.1021/acs.jmedchem.2c01491]

9. Wang XR, Wang S, Mu HX, Xu KY, Wang XT, Shi JT, Cui QH, Zhang LW, Chen SW..  (2022)  Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer.,  244  [PMID:36242985] [10.1016/j.ejmech.2022.114821]

10. Han X, Wang C, Qin C, Xiang W, Fernandez-Salas E, Yang CY, Wang M, Zhao L, Xu T, Chinnaswamy K, Delproposto J, Stuckey J, Wang S..  (2019)  Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer.,  62  (2): [PMID:30629437] [10.1021/acs.jmedchem.8b01631]

Source

Source(1):

• Scientific Literature