571190-30-2 Usage
Description
Palbociclib 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.
Uses
Palbociclib (also known as compound number PD-0332991) is an experimental drug for the treatment of breast cancer being developed by Pfizer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.
Definition
ChEBI: 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.
Indications
Palbociclib (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.
Biochem/physiol Actions
PF-00080665 (Palbociclib; PD 0332991) is an orally active and highly specific inhibitor against cyclin-dependent kinase 4 & 6 (IC50 = 9, 11, 15 nM, respectively, using CDK4/cycD3, CDK4/cycD1, CDK6/cycD2; IC50 >10 μM against 36 other kinases) that potently suppresses Cdk4/6-dependent cellular Rb phosphorylation (IC50 = 66 nM/pSer780 & 63 nM/pSer795; MDA-MB-435). PF-00080665 exhibits selective antiproliferation activity against Rb-positive human breast/colon/lung/leukemia cancer cultures (IC50 = 40-400 nM; IC50 >3 μM/Rb-negative MDA-MB-468 & H2009) and displays in vivo efficacy against various advanced stage human tumor xenografts in mice (12.5-150 mg/kg/day p.o.).
Clinical Use
Protein kinase inhibitor:
Treatment of hormone receptor (HR)-positive,
human epidermal growth factor receptor 2 (HER2)-
negative locally advanced or metastatic breast cancer
Synthesis
Numerous 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 inhibitor
This 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).
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by
clarithromycin - avoid or reduce palbociclib dose;
concentration reduced by rifampicin - avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by
carbamazepine, fosphenytoin and phenytoin - avoid.
Antifungals: concentration possibly increased
by itraconazole, ketoconazole, posaconazole and
voriconazole - avoid or reduce palbociclib dose.
Antipsychotics: increased risk of agranulocytosis
with clozapine - avoid.
Antivirals: concentration possibly increased by
indinavir, lopinavir, ritonavir, saquinavir and
telaprevir - avoid or reduce palbociclib dose.
Cytotoxics: concentration possibly reduced by
enzalutamide - avoid.
Grapefruit juice: concentration possibly increased -
avoid
Metabolism
Palbociclib undergoes extensive hepatic metabolism.
The main metabolic pathways for palbociclib involved
oxidation and sulphonation, with acylation and
glucuronidation contributing as minor pathways.
Unchanged drug accounts for 2.3% and 6.9% of
radioactivity in faeces and urine, respectively. In faeces,
the sulfamic acid conjugate of palbociclib was the major
drug-related component, accounting for 26% of the
administered dose.
References
1) El-Rayes?et al.?(2004),?Cyclooxygenase-2-dependent and –independent effects of celecoxib in pancreatic cancer cell lines; Mol. Cancer Ther.,?3?1427
2) Menu?et al.?(2008),?A novel therapeutic combination using PD 0332991 and bortezomib: study in 5T33MM myeloma model; Cancer Res.,?68?5519
3) Valenzuela?et al.?(2017),?Palbociclib-induced autophagy and senescence in gastric cancer cells; Exp. Cell Res.,?360?390
4) Palanisamy?et al.?(2016),?Palbociclib: A new hope in the treatment of breast cancer; J. Cancer Res. Ther.,?12?1220
5) Goel?et al.?(2017),?CDK4/6 inhibition triggers anti-tumour immunity; Nature?548?471
6)6) AbuHammad?et al.?(2019),?Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma; Proc. Natl. Acad. Sci. USA?116?179909
Check Digit Verification of cas no
The CAS Registry Mumber 571190-30-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 5,7,1,1,9 and 0 respectively; the second part has 2 digits, 3 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 571190-30:
(8*5)+(7*7)+(6*1)+(5*1)+(4*9)+(3*0)+(2*3)+(1*0)=142
142 % 10 = 2
So 571190-30-2 is a valid CAS Registry Number.
InChI:InChI=1/C24H29N7O2/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29)
571190-30-2Relevant articles and documents
Preparation method of palbociclib
-
, (2021/06/09)
The invention provides a preparation method of palbociclib. Specifically, ethyl acetoacetate and acetaldehyde are subjected to condensation hydrolysis to prepare 2-acetyl-2-butenoic acid instead of crotonic acid, and tedious steps such as acetyl group loading are not needed, so a synthesis route is simplified. The preparation method is simple and safe, product purity is high, and product yield is improved.
Low-cost preparation method of palbociclib
-
Paragraph 0078-0081, (2021/11/26)
The invention discloses a low-cost preparation method of palbociclib. The method comprises the steps: taking 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester as an initial raw material, taking large-steric-hindrance alkali as an acid-binding agent, carrying out nucleophilic substitution reaction with a compound represented by a formula 3, carrying out post-treatment, quenching and dealkalizing to obtain a large-particle compound represented by a formula 4; then taking n-butyl alcohol and water as solvents, taking diisopropylethylamine as an acid-binding agent and a protective agent, and under the action of a composite catalyst palladium chloride and cuprous iodide, carrying out a Herk alkylation reaction with n-butyl vinyl ether; and under the protection of an organic alkali, refining with an ester solvent to obtain a high-purity compound represented by a formula 5 with high yield, and hydrolyzing the compound represented by the formula 5 through a mixed solvent of n-butyl alcohol, anisole and water under an acidic condition to obtain a finished product of palbociclib. The method greatly reduces the usage amount of a palladium catalyst, and is simple and convenient to operate, less in environmental pollution, high in yield, high in product quality and more suitable for industrial production.
Method for synthesizing palbociclib
-
Paragraph 0014; 0027-0032, (2019/07/11)
The invention discloses a method for synthesizing palbociclib. The method comprises the following steps: 1, carrying out a coupled reaction on a compound as shown in a formula (II) and a compound as shown in a formula (III) under the action of cyclohexylmagnesium chloride to obtain a compound as shown in a formula (IV); 2, reacting the compound as shown in the formula (IV) with magnesium metal toprepare a Grignard reagent, then, carrying out a Grignard reaction on the Grignard reagent and carbon dioxide, and carrying out hydrolysis to prepare a compound as shown in a formula (V); and 3, reacting the compound as shown in the formula (V) with acetic anhydride under the action of alkaline to obtain a crude product, and deprotecting the crude product under the action of an acid to prepare a target product. The method for synthesizing palbociclib, disclosed by the invention, is cheap and available in raw materials, high in synthesis efficiency, few in impurity, easy to control and suitablefor industrial production and provides a new approach for synthesizing palbociclib.
