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Palbociclib

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Palbociclib Basic information
Palbociclib Chemical Properties
  • Melting point:200 ºC
  • Boiling point:711.5±70.0 °C(Predicted)
  • Density 1.313±0.06 g/cm3(Predicted)
  • storage temp. room temp
  • pka8.66±0.10(Predicted)
  • form powder
  • color white to beige
Palbociclib Usage And Synthesis
  • DescriptionPalbociclib is a cyclin-dependent kinase (CDK) 4 and CDK6 inhibitor approved by the FDA to treat hormone receptor-positive (HR+) human epidural growth factor 2-negative (HER2-) metastatic breast cancer. It is used in combination with letrazole as the first-line hormonal-based therapy in postmenopausal women, or with fulvestrant in women with disease progression following hormonal therapy. Palbociclib was discovered at Warner- Lambert and developed by Pfizer after their merger. Pfizer is also studying the effectiveness of palbociclib in a variety of other cancers at various stages in the clinic.
  • DefinitionChEBI: A member of the class of pyridopyrimidines that is 2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7-one bearing additional methyl, acetyl and cyclopentyl substituents at positions 5, 6 and 8 respectively. It is used in combina ion with letrozole for the treatment of metastatic breast cancer.
  • IndicationsPalbociclib (Ibrane(R), Pfizer), a selective CDK4 and CDK6 inhibitor, received accelerated approval from FDA in 2015 for women with estrogen receptor-positive and HER2-negative breast cancer in combination with letrozole.
  • Chemical SynthesisNumerous syntheses of palbociclib have been reported,149,150 and the commercial scale process published by scientists at Pfizer is described herein. The amino-pyridylpiperazine fragment 212 was prepared in two steps. Commercial piperazine 209 was added to 5-bromo-2-nitropyridine (210) to give nitro-pyridine 211 in 93% yield. Hydrogenation of the nitro group using catalytic palladium on carbon provided the amino-pyridylpiperazine 212 in 96% yield.
    As such, cyclopentylamine (214) was added to 5-bromo-2,4-dichloropyrimidine (213) to give 5-bromo-2-chloro-6-cyclopentylaminopyrimidine (215) in 84% yield. Heck reaction with crotonic acid followed by treating the resulting product with acetic anhydride formed the mixed anhydride under elevated temperatures, and this resulted in cyclization to give pyrimidinone 214 in 81% yield. Bromination using N-bromosuccinimide (NBS) provided coupling partner 217 in 88% yield. Next, aminopyridine 212 was treated with cyclohexylmagnesium chloride and then reacted with 217 to give the SNAr product 218 in 88% yield. A second Heck reaction between bromide 218 and butyl vinyl ether (219) using palladium acetate/bis(2- diphenylphosphinophenyl)ether (DPEPhos) as the catalyst provided enol ether 220 in 84% yield. Exposure of 220 to acidic conditions removed the Boc group from the piperazine while converting the enol ether to the corresponding ketone, providing palbociclib (XXVII) in 90% yield.

  • Enzyme inhibitorThis orally active, non-ATP-competitive cyclin kinase-directed inhibitor (FW = 483.99 g/mol (mono-HCl); CASs = 827022-32-2 (mono- hydrochloride, 571190-30-2 (free base); Solubility: 10 mg/mL DMSO; 30 mg/mL Water; Formulation: Dissolved in sodium lactate buffer (50 mM, ® pH 4.0) ), also known as PD-0332991, Ibrance, and 6-acetyl-8-cyclopentyl- 5-methyl-2- (5- (piperazin-1-yl) pyridin-2-ylamino) pyrido[2,3-d]pyrimidin- 7 (8H) -one hydrochloride, targets Cdk-4 (Cyclin D1) and Cdk-6 (Cyclin D2), enzymes that participate in the so-called CDK4/6-retinoblastoma signaling pathway governing the cell-cycle restriction point. Palbociclib induces rapid G1 cell-cycle arrest in primary human myeloma cells. This agent also shows significant efficacy in a broad spectrum of human tumor xenografts in vivo, resulting in complete regression in some tumors with no evidence of acquired resistance or ability to circumvent the growth inhibitory properties of this agent. Ibrance received FDA approval in 2015 for combined use with letrozole to treat postmenopausal women with estrogen receptor- positive, (HER2) -negative advanced breast cancer as an initial endocrine- based therapy for metastatic disease. Cyclin Target Selectivity: Cdk1 (weak, if any), Cdk2 (weak, if any), Cdk3 (weak, if any), Cdk4 (IC50 = 11 nM), Cdk5 (weak, if any), Cdk6 (IC50 = 16 nM), Cdk7 (weak, if any), Cdk8 (weak, if any), Cdk9 (weak, if any), Cdk10 (weak, if any).
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