2015 Jul 21. doi: 10.1002/cmdc.201500218. [Epub ahead of print]
Nettekoven M1, Adam JM2, Bendels S2, Bissantz C2, Fingerle J3, Grether U2, Grüner S3, Guba W2, Kimbara A2, Ottaviani G4, Püllmann B2, Rogers-Evans M2, Röver S2, Rothenhäusler B4, Schmitt S2, Schuler F4, Schulz-Gasch T2, Ullmer C3.
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.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
KEYWORDS:
CB2 receptor agonists; fibrosis; inflammation; lead optimization; triazolopyrimidines
- PMID:
- 26228928
- [PubMed – as supplied by publisher]