| Reference | 1. Antimicrob Agents Chemother. 2014 Jun;58(6):3233-44. doi: 10.1128/AAC.02719-13.
Epub 2014 Mar 24.
<br>
Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase
inhibitor.
<br>
Fenwick C(1), Amad M(2), Bailey MD(2), Bethell R(2), Bös M(2), Bonneau P(2),
Cordingley M(2), Coulombe R(2), Duan J(2), Edwards P(2), Fader LD(1), Faucher
AM(2), Garneau M(2), Jakalian A(2), Kawai S(2), Lamorte L(2), LaPlante S(2), Luo
L(2), Mason S(2), Poupart MA(2), Rioux N(2), Schroeder P(2), Simoneau B(2),
Tremblay S(2), Tsantrizos Y(2), Witvrouw M(2), Yoakim C(2).
<br>
Author information: <br>
(1)Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada)
Ltd., Research and Development, Laval, QC, Canada [email protected]
[email protected].
(2)Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada)
Ltd., Research and Development, Laval, QC, Canada.
<br>
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 has a low, ～2.1-fold decrease in antiviral potency in the presence
of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits
serum-shifted EC95 values ranging between 22 and 75 nM. Passage of virus in the
presence of inhibitor selected for either A128T, A128N, or L102F primary
resistance substitutions, all mapping to a conserved allosteric pocket on the
catalytic core of integrase. 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,
<br>
2. ACS Med Chem Lett. 2014 Jan 22;5(4):422-7. doi: 10.1021/ml500002n. eCollection
2014 Apr 10.
<br>
Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.
<br>
Fader LD(1), Malenfant E(1), Parisien M(1), Carson R(1), Bilodeau F(1), Landry
S(1), Pesant M(1), Brochu C(1), Morin S(1), Chabot C(1), Halmos T(1), Bousquet
Y(1), Bailey MD(1), Kawai SH(1), Coulombe R(1), LaPlante S(1), Jakalian A(1),
Bhardwaj PK(1), Wernic D(1), Schroeder P(1), Amad M(1), Edwards P(1), Garneau
M(1), Duan J(1), Cordingley M(1), Bethell R(1), Mason SW(1), Bös M(1), Bonneau
P(1), Poupart MA(1), Faucher AM(1), Simoneau B(1), Fenwick C(1), Yoakim C(1),
Tsantrizos Y(1).
<br>
Author information: <br>
(1)Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard
Street, Laval, Québec H7S 2G5, Canada.
<br>
An assay recapitulating the 3/’ processing activity of HIV-1 integrase (IN) was
used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead
optimization beginning with compound 1 established the importance of the C3 and
C4 substituent to antiviral potency against viruses with different aa124/aa125
variants of IN. The importance of the C7 position on the serum shifted potency
was established. Introduction of a quinoline substituent at the C4 position
provided a balance of potency and metabolic stability. Combination of these
findings ultimately led to the discovery of compound 26 (BI 224436), the first
NCINI to advance into a phase Ia clinical trial.
<br>
|
