title: Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor.
abstract: 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, BI 224436 was advanced into phase 1 clinical trials.
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada Craig.Fenwick@chuv.ch lee.fader@boehringer-ingelheim.com.
authors.forename: Craig
authors.initials: C
authors.lastname: Fenwick
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Ma'an
authors.initials: M
authors.lastname: Amad
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Bethell
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Bös
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Cordingley
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Edwards
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada Craig.Fenwick@chuv.ch lee.fader@boehringer-ingelheim.com.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Fader
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faucher
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kawai
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Louie
authors.initials: L
authors.lastname: Lamorte
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: LaPlante
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Laibin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Mason
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Poupart
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Schroeder
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Tremblay
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Youla
authors.initials: Y
authors.lastname: Tsantrizos
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Myriam
authors.initials: M
authors.lastname: Witvrouw
authors.affiliation: Biological Sciences and Chemistry Departments, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, QC, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Yoakim
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D018938:Caco-2 Cells; D003001:Cloning, Molecular; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004279:DNA, Viral / Q000187:drug effects; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D051381:Rats; D044967:Serum / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1