title: Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.
abstract: Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
authors.affiliation: Medicinal Chemistry Berlin, Bayer HealthCare AG, 13353 Berlin (Germany). franz.nussbaum@bayer.com.
authors.forename: Franz
authors.initials: F
authors.lastname: von Nussbaum
authors.affiliation: Lead Discovery Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany). volkhart.li@bayer.com.
authors.forename: Volkhart M-J
authors.initials: VM
authors.lastname: Li
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Swen
authors.initials: S
authors.lastname: Allerheiligen
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Sonja
authors.initials: S
authors.lastname: Anlauf
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Lars
authors.initials: L
authors.lastname: Bärfacker
authors.affiliation: Department of Cardiology Research Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Martin
authors.initials: M
authors.lastname: Bechem
authors.affiliation: Department of Cardiology Research Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Martina
authors.initials: M
authors.lastname: Delbeck
authors.affiliation: COPD Research, Bayer Healthcare AG, Slough SL2 4LY, Berkshire (UK).
authors.forename: Mary F
authors.initials: MF
authors.lastname: Fitzgerald
authors.affiliation: DMPK Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Michael
authors.initials: M
authors.lastname: Gerisch
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Heike
authors.initials: H
authors.lastname: Gielen-Haertwig
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Helmut
authors.initials: H
authors.lastname: Haning
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Dagmar
authors.initials: D
authors.lastname: Karthaus
authors.affiliation: DMPK Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Dieter
authors.initials: D
authors.lastname: Lang
authors.affiliation: DMPK Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Klemens
authors.initials: K
authors.lastname: Lustig
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Daniel
authors.initials: D
authors.lastname: Meibom
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Joachim
authors.initials: J
authors.lastname: Mittendorf
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rosentreter
authors.affiliation: Lead Discovery, Structural Biology Berlin, Bayer HealthCare AG, 13353 Berlin (Germany).
authors.forename: Martina
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Department of Cardiology Research Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Stefan
authors.initials: S
authors.lastname: Schäfer
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Jens
authors.initials: J
authors.lastname: Schamberger
authors.affiliation: Medicinal Chemistry Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Leila A
authors.initials: LA
authors.lastname: Telan
authors.affiliation: Lead Discovery Wuppertal, Bayer HealthCare AG, 42096 Wuppertal (Germany).
authors.forename: Adrian
authors.initials: A
authors.lastname: Tersteegen
mesh_terms: D004305:Dose-Response Relationship, Drug; D005615:Freezing; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008171:Lung Diseases / Q000201:enzymology*; D008968:Molecular Conformation; D053491:Proteinase Inhibitory Proteins, Secretory / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000606490:BAY 85-8501; D053491:Proteinase Inhibitory Proteins, Secretory; D011744:Pyrimidinones; D013450:Sulfones; D019272:Leukocyte Elastase
keywords: biginelli reaction; biological activity; elastase inhibitors; proteases; pyrimidinones