PF-4136309

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H31F3N6O3
Molecular Weight	568.59
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O[C@]1(CC[C@@H](CC1)N[C@H]2CCN(C2)C(=O)CNC(=O)C3=CC=CC(=C3)C(F)(F)F)C4=NC=C(C=C4)C5=NC=CC=N5

InChI

InChIKey=ZNSVOHSYDRPBGI-LXWOLXCRSA-N

InChI=1S/C29H31F3N6O3/c30-29(31,32)21-4-1-3-19(15-21)27(40)36-17-25(39)38-14-9-23(18-38)37-22-7-10-28(41,11-8-22)24-6-5-20(16-35-24)26-33-12-2-13-34-26/h1-6,12-13,15-16,22-23,37,41H,7-11,14,17-18H2,(H,36,40)/t22-,23-,28-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C29H31F3N6O3
Molecular Weight	568.59
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900280 | http://adisinsight.springer.com/drugs/800026843
Curator's Comment: Description was created based on several sources, including https://newdrugapprovals.org/tag/incb-8761/

INCB-8761 (PF-4136309) is an orally available human chemokine receptor 2 (CCR2) antagonist with potential immunomodulating and antineoplastic activities. Upon oral administration, CCR2 antagonist INCB-8761 specifically binds to CCR2 and prevents binding of the endothelium-derived chemokine ligand CLL2 (monocyte chemoattractant protein-1 or MCP1) to its receptor CCR2, which may result in inhibition of CCR2 activation and signal transduction. This may inhibit inflammatory processes as well as angiogenesis, tumor cell migration, and tumor cell proliferation. INCB-8761 is a potent CCR2 antagonist with high selectivity, weak hERG activity, high free fraction in protein binding, and an excellent in vitro and in vivo ADMET (ADME and toxicology) profile. INCB-8761 entered human clinical trials. It is in phase I/II clinical trials for pancreatic cancer.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
C-C chemokine receptor type 2 19 Target ID: CHEMBL4015 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900280	Antagonist 2849		5.2 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pancreatic cancer 98 Sources: https://clinicaltrials.gov/ct2/show/NCT01413022 http://adisinsight.springer.com/drugs/800026843 https://clinicaltrials.gov/ct2/show/NCT02732938	Primary		Phase II 1147	Unknown Approved Use Unknown

F_unbound

Value	Dose	Co-administered	Analyte	Population
4% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11959574/			DEXELVUCITABINE serum	Homo sapiens

PubMed

Title	Date	PubMed
Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist.	2011-12-08	24900280

Patents

Sample Use Guides

In Vivo Use Guide

INCB-8761 (PF-4136309) 500 mg PO BID on days 1-14 Treatment for pancreatic neoplasms included: Experimental: Group B (FOLFIRINOX and PF-04136309) Patients receive FOLFIRINOX chemotherapy comprising of: oxaliplatin 85 mg/m2 IV on Day 1 irinotecan 180 mg/m2 IV on Day 1 leucovorin 400 mg/m2 IV on Day 1 5FU 400 mg/m2 bolus and 2400 mg/m2 CIVI over 46 hours beginning on Day 1 INCB-8761 (PF-4136309) 500 mg PO BID on days 1-14

Route of Administration: Oral

In Vitro Use Guide

In signaling assays, INCB-8761 is potent in inhibiting CCR2 mediated signaling events such as intracellular calcium mobilization and ERK (extracellular signal-regulated kinase) phosphorylation with IC50 values of 3.3 and 0.5 nM, respectively. Cerep screens revealed that INCB-8761 is a selective CCR2 inhibitor, showing no significant inhibitory activity at a concentration of 1 uM when tested against a panel of >50 ion channels, transporters, chemokine receptors including CCR1, CCR3, CCR5, CXCR3, and CXCR5, and additional GPCRs. In hERG patch clamp assay, INCB-8761 inhibited hERG potassium current with an IC50 of 20 uM.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:31:41 GMT 2025` Edited by `admin` on `Mon Mar 31 18:31:41 GMT 2025`
Record UNII	3M2595V4KT
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PF-4136309

Code

English

INCB-8761

Preferred Name

English

BENZAMIDE, N-(2-((3S)-3-((TRANS-4-HYDROXY-4-(5-(2-PYRIMIDINYL)- 2-PYRIDINYL)CYCLOHEXYL)AMINO)-1-PYRROLIDINYL)-2-OXOETHYL)-3-(TRIFLUOROMETHYL)-

Systematic Name

English

INCB8761

Code

English

N-(2-((3S)-3-((TRANS-4-HYDROXY-4-(5-(PYRIMIDIN-2-YL)PYRIDIN-2- YL)CYCLOHEXYL)AMINO)PYRROLIDIN-1-YL)-2-OXOETHYL)-3-(TRIFLUOROMETHYL)BENZAMIDE

Systematic Name

English

PF-04136309

Code

English

PF-4136309 [WHO-DD]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

570416