U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C27H26N2O4
Molecular Weight 442.5074
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of BI-224436

SMILES

Cc1c(c(c2ccccc2n1)-c3ccc4c5c(ccnc35)CCO4)[C@@]([H])(C(=O)O)OC(C)(C)C

InChI

InChIKey=MIXIIJCBELCMCZ-VWLOTQADSA-N
InChI=1S/C27H26N2O4/c1-15-21(25(26(30)31)33-27(2,3)4)23(17-7-5-6-8-19(17)29-15)18-9-10-20-22-16(12-14-32-20)11-13-28-24(18)22/h5-11,13,25H,12,14H2,1-4H3,(H,30,31)/t25-/m0/s1

HIDE SMILES / InChI

Molecular Formula C27H26N2O4
Molecular Weight 442.5074
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment:: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/24666332 https://www.ncbi.nlm.nih.gov/pubmed/23413196

BI-224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 μM. BI-224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI-224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI-224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials. Trials with clinical candidate BI-224436 were put on hold despite promising results.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
7.2 nM [EC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG



OverviewOther

Other InhibitorOther SubstrateOther Inducer




Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
unlikely [IC50 >30 uM]
unlikely [IC50 >30 uM]
unlikely [IC50 >30 uM]
yes [IC50 20 uM]
yes [IC50 23 uM]
Drug as victim

Drug as victim

PubMed

PubMed

TitleDatePubMed
Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.
2014 Apr 10
Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor.
2014 Jun
Patents

Patents

Sample Use Guides

Single rising oral doses of BI-224436 ZW at 6.2 mg, 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 900 mg and 1200 mg
Route of Administration: Oral
In the PBMCs, BI-224436 had EC50s of 7.2 nM, 14 nM, and 15 nM observed for HXB2, NL4.3, and BaL integrase-containing viruses, respectively
Substance Class Chemical
Created
by admin
on Sat Jun 26 08:11:19 UTC 2021
Edited
by admin
on Sat Jun 26 08:11:19 UTC 2021
Record UNII
99A996378Y
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
BI-224436
Code English
BI224436
Code English
3-QUINOLINEACETIC ACID, 4-(2,3-DIHYDROPYRANO(4,3,2-DE)QUINOLIN-7-YL)-.ALPHA.-(1,1-DIMETHYLETHOXY)-2-METHYL-, (.ALPHA.S,4R)-
Systematic Name English
Code System Code Type Description
CAS
1155419-89-8
Created by admin on Sat Jun 26 08:11:19 UTC 2021 , Edited by admin on Sat Jun 26 08:11:19 UTC 2021
NON-SPECIFIC STEREOCHEMISTRY
FDA UNII
99A996378Y
Created by admin on Sat Jun 26 08:11:19 UTC 2021 , Edited by admin on Sat Jun 26 08:11:19 UTC 2021
PRIMARY
PUBCHEM
66561902
Created by admin on Sat Jun 26 08:11:19 UTC 2021 , Edited by admin on Sat Jun 26 08:11:19 UTC 2021
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
TARGET ORGANISM->INHIBITOR
Related Record Type Details
ACTIVE MOIETY