571190-30-2

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.).

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.

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.