title: Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases.
abstract: The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small-molecule CB2 receptor agonists were identified from a high-throughput screen. Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure-activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3S)-1-[5-tert-butyl-3-[(1-cyclopropyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol (39), was tested in a kidney ischemia-reperfusion model, in which it showed efficacy at a dose of 10 mg kg(-1) (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis. Oral treatment with 39 at 3 mg kg(-1) per day significantly decreased the amount of fibrosis by ∼ 40% which was induced by unilateral ureter obstruction.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland. matthias.nettekoven@roche.com.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nettekoven
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Adam
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bendels
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Catarina
authors.initials: C
authors.lastname: Bissantz
authors.affiliation: Roche Pharmaceutical Research and Early Development, Discovery Biology, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Fingerle
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Grether
authors.affiliation: Roche Pharmaceutical Research and Early Development, Discovery Biology, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grüner
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kimbara
authors.affiliation: Roche Pharmaceutical Research and Early Development, DMPK, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ottaviani
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Püllmann
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Rogers-Evans
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Röver
authors.affiliation: Roche Pharmaceutical Research and Early Development, DMPK, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Benno
authors.initials: B
authors.lastname: Rothenhäusler
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Roche Pharmaceutical Research and Early Development, DMPK, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Franz
authors.initials: F
authors.lastname: Schuler
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small-Molecule Research, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schulz-Gasch
authors.affiliation: Roche Pharmaceutical Research and Early Development, Discovery Biology, Roche Innovation Center Basel, Grenzacher Str. 124, 4070, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ullmer
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007674:Kidney Diseases / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C588309:CNR2 protein, human; D063386:Cannabinoid Receptor Agonists; D011743:Pyrimidines; D043885:Receptor, Cannabinoid, CB2; D014230:Triazoles
keywords: CB2 receptor agonists; fibrosis; inflammation; lead optimization; triazolopyrimidines