1341224-83-6

Basic information

• Product Name: INCB8761(PF-4136309)
• Synonyms: INCB8761(PF-4136309);NCB8761(PF-4136309);PF-04136309(INCB-8761);Benzamide, N-[2-[(3S)-3-[[trans-4-hydroxy-4-[5-(2-pyrimidinyl)-2-pyridinyl]cyclohexyl]amino]-1-pyrrolidinyl]-2-oxoethyl]-3-(trifluoromethyl)-;EOS-61910;N-(2-((S)-3-(((1r,4S)-4-hydroxy-4-(5-(pyrimidin-2-yl) yridine-2-yl)cyclohexyl)amino)pyrrolidin-1-yl)-2-oxoethyl)-3-(trifluoromethyl)benzamide;ZNSVOHSYDRPBGI-LXWOLXCRSA-N
• CAS NO: 1341224-83-6
• Molecular Formula: C₂₉H₃₁F₃N₆O₃
• Molecular Weight: 568.5900496
• Mol File: 1341224-83-6.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 712.2±60.0 °C(Predicted)
• Appearance: /
• Density: 1.40±0.1 g/cm3(Predicted)
• Storage Temp.: Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
• Solubility: Soluble in DMSO (up to at least 25 mg/ml)
• PKA: 13.17±0.46(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: INCB8761(PF-4136309)(CAS DataBase Reference)
• NIST Chemistry Reference: INCB8761(PF-4136309)(1341224-83-6)
• EPA Substance Registry System: INCB8761(PF-4136309)(1341224-83-6)

Safety Data

• Hazardous Substances Data: 1341224-83-6(Hazardous Substances Data)

Usage

Description

PF-4136309 is a chemokine (C-C motif) receptor 2 (CCR2) antagonist (IC50s = 5.2, 13, and 17 nM for the human, rat, and mouse receptors, respectively). It also inhibits the voltage-gated potassium channel subtype Kv11.1 by 35% when used at a concentration of 10 μM. PF-4136309 decreases isolated human monocyte chemotaxis induced by chemokine (C-C motif) ligand 2 (CCL2) with an IC50 value of 3.9 nM.

Uses

PF 4136309 is a CCR5 receptor antagonists that contributes to the treatment of rheumatoid arthritis.

References

1) Chu-Biao?et al.?(2011),?Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist;?ACS Med. Chem. Lett.?2?913 2) Sanford?et al.?(2013),?Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis;?Clin. Cancer Res.?19?3404 3) Nywenig?et al.?(2016),?Phase 1b study targeting tumor associated macrophages with CCR2 inhibition plus FOLFIRINOX in locally advanced and borderline resectable pancreatic cancer;?Lancet Oncol.?17?651

Synthetic route

4-hydroxy-4-(5-(pyrimidin-2-yl)pyridin-2-yl)cyclohexanone (857651-06-0) + (S)-N-{2-[3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide hydrochloride (857651-01-5) → PF-4136309 (1341224-83-6)

Conditions	Yield
Stage #1: 4-hydroxy-4-(5-(pyrimidin-2-yl)pyridin-2-yl)cyclohexanone; (S)-N-{2-[3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide hydrochloride With triethylamine In 2-methyl-propan-1-ol for 0.5h; Cooling with ice; Stage #2: With sodium tris(acetoxy)borohydride In 2-methyl-propan-1-ol at 20℃; for 4h;	66%

2,5-dibromopyridine (624-28-2) → PF-4136309 (1341224-83-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene / 2.5 h / -78 °C 1.2: -78 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 3.67 h / 25 °C / Inert atmosphere 2.2: 25 °C / Inert atmosphere 3.1: hydrogenchloride / tetrahydrofuran; water / 1 h / 20 - 25 °C 4.1: triethylamine / 2-methyl-propan-1-ol / 0.5 h / Cooling with ice 4.2: 4 h / 20 °C View Scheme

cyclohexanedione monoethylene ketal (4746-97-8) → PF-4136309 (1341224-83-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene / 2.5 h / -78 °C 1.2: -78 - 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 3.67 h / 25 °C / Inert atmosphere 2.2: 25 °C / Inert atmosphere 3.1: hydrogenchloride / tetrahydrofuran; water / 1 h / 20 - 25 °C 4.1: triethylamine / 2-methyl-propan-1-ol / 0.5 h / Cooling with ice 4.2: 4 h / 20 °C View Scheme

8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (708274-37-7) → PF-4136309 (1341224-83-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3.67 h / 25 °C / Inert atmosphere 1.2: 25 °C / Inert atmosphere 2.1: hydrogenchloride / tetrahydrofuran; water / 1 h / 20 - 25 °C 3.1: triethylamine / 2-methyl-propan-1-ol / 0.5 h / Cooling with ice 3.2: 4 h / 20 °C View Scheme

8-(5-pyrimidin-2-ylpyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (857651-05-9) → PF-4136309 (1341224-83-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / tetrahydrofuran; water / 1 h / 20 - 25 °C 2.1: triethylamine / 2-methyl-propan-1-ol / 0.5 h / Cooling with ice 2.2: 4 h / 20 °C View Scheme

m-trifluoromethylhippuric acid (17794-48-8) → PF-4136309 (1341224-83-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 20 °C / Cooling with ice 2.1: hydrogenchloride / 1,4-dioxane; methanol / 1 h / 20 °C 3.1: triethylamine / 2-methyl-propan-1-ol / 0.5 h / Cooling with ice 3.2: 4 h / 20 °C View Scheme

Upstream product

• 17794-48-8 m-trifluoromethylhippuric acid 
• 857651-06-0 4-hydroxy-4-(5-(pyrimidin-2-yl)pyridin-2-yl)cyclohexanone 
• 857651-01-5 (S)-N-{2-[3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide hydrochloride 
• 857651-05-9 8-(5-pyrimidin-2-ylpyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol 
• 708274-37-7 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol 
• 4746-97-8 cyclohexanedione monoethylene ketal 
• 624-28-2 2,5-dibromopyridine 

Relevant articles and documents

Discovery of INCB8761/PF-4136309, a potent, selective, and orally bioavailable CCR2 antagonist

We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high sel