5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine

• ChemBase ID: 5722
• Molecular Formular: C18H21F2N5O4S
• Molecular Mass: 441.4522464
• Monoisotopic Mass: 441.12823162
• SMILES: N1(CCC(CC1)Nc1ncc(c(n1)N)C(=O)c1c(c(ccc1OC)F)F)S(=O)(=O)C
• Canonical SMILES: COc1ccc(c(c1C(=O)c1cnc(nc1N)NC1CCN(CC1)S(=O)(=O)C)F)F
• InChI: InChI=1S/C18H21F2N5O4S/c1-29-13-4-3-12(19)15(20)14(13)16(26)11-9-22-18(24-17(11)21)23-10-5-7-25(8-6-10)30(2,27)28/h3-4,9-10H,5-8H2,1-2H3,(H3,21,22,23,24)
• InChIKey: JRNJNYBQQYBCLE-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine
• IUPAC Traditional name: 5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine
• Synonyms: R547; (4-AMINO-2-{[1-(METHYLSULFONYL)PIPERIDIN-4-YL]AMINO}PYRIMIDIN-5-YL)(2,3-DIFLUORO-6-METHOXYPHENYL)METHANONE

Database IDs

• CAS Number: 741713-40-6
• PubChem SID: 160969149; 99444565
• PubChem CID: 6918852

CALCULATED PROPERTIES

JChem

• Acid pKa: 14.5448065
• H Acceptors: 8
• H Donor: 2
• LogD (pH = 5.5): 0.3789153
• LogD (pH = 7.4): 0.9363782
• Log P: 0.9526561
• Molar Refractivity: 108.6708 cm^3
• Polarizability: 40.217087 Å^3
• Polar Surface Area: 127.51 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 1.57
• LOG S: -3.41
• Solubility (Water): 1.72e-01 g/l

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: CDK

Product Information

• Salt Data: Free Base

DETAILS

DrugBank - DB08094

Drug information: experimental

Selleck Chemicals - S2688

Biological Activity

• Description: R547 is a potent and selective CDK inhibitor with K_i and IC50 of 1-3 nM and 80 nM respectively.
• Targets: CDK
• IC50: 80 nM ^[2]
• In Vitro: R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. R547 effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1(Ki=1–3nM) and is inactive(Ki>5,000nM) against a panel of >120 unrelated kinases. R547 effectively inhibits the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s <0.60 μm.="" r547="" reduces="" phosphorylation="" of="" the="" cellular="" retinoblastoma="" protein="" at="" specific="" cdk="" phosphorylation="" sites="" at="" the="" same="" concentrations="" that="" induced="" cell="" cycle="" arrest,="" suggesting="" a="" potential="" pharmaco="" dynamics="" marker="" for="" clinical="" use.="" r547="" inhibits="" the="" proliferation="" of="" tumor="" cell="" lines="" and="" is="" active="" in="" all="" 19="" cell="" lines="" tested="" irrespective="" of="" tissue="" of="" origin,="" multidrug="" resistance="" (mdr),="" p53,="" or="" retinoblastoma="" status.="">^[1] R547 possessing both 5-and 6-fluoro substitution culminated in an Inhibitor with low, single-digit nanomolar potency against the CDKs(Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively) and excellent cellular potency (IC50=0.08 μM,HCT116 cell line). ^[2]
• In Vivo: R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01).="" r547="" administered="" orally="" at="" dose="" of="" 40="" mg/kg="" daily="" in="" colon,="" lung,="" breast,="" prostate,="" and="" melanoma="" human="" tumor="" xenograft="" models="" shows="" significant="" tgi="" (79–99%).="" r547="" is="" equally="" efficacious="" (tgi,="" 61–95%)="" when="" dosed="" with="" 40="" mg/kg="" i.v.="" once="" weekly.="" these="" doses="" of="" r547="" are="" not="" toxic="" and="" did="" not="" result="" in="" body="" weight="" loss.="" r547="" does="" not="" show="" signs="" of="" overt="" toxicity="" during="" the="" course="" of="" the="" 3-week="" study="" and="" any="" gross="" pathology="" at="" necropsies="" done="" at="" the="" end="" of="" the="" studies.="">^[1] R547 inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . R547 causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. R547 inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. R547 reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. ^[2]
• Clinical Trials: R547 is currently in Phase I clinical trial for the treatment of cancer.

References

• References: [1] Rodriguez A , et al. Mol Cancer Ther, 2006, 5(11), 2644-2658.
• References: [2] Chu XJ, et al. J Med Chem, 2006, 49(22), 6549-6560.
• References: [3] Berkofsky-Fessler W, et al. Mol Cancer Ther, 2009, 8(9), 2517-2525.

REFERENCES

• Rodriguez A , et al. Mol Cancer Ther, 2006, 5(11), 2644-2658.
• Chu XJ, et al. J Med Chem, 2006, 49(22), 6549-6560.
• Berkofsky-Fessler W, et al. Mol Cancer Ther, 2009, 8(9), 2517-2525.