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ID: ALA4725439
Journal: ACS Med Chem Lett
Title: Direct Comparison of (N)-Methanocarba and Ribose-Containing 2-Arylalkynyladenosine Derivatives as A Receptor Agonists.
Authors: Tosh DK,Salmaso V,Rao H,Campbell R,Bitant A,Gao ZG,Auchampach JA,Jacobson KA
Abstract: A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]hexane) nucleosides as AAR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse AAR. The mean affinity enhancement for 5 pairs of 5'-methylamides was 11-fold at hAAR and 42-fold at mAAR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hAAR-selective 16 (MRS7334) displaying K 280 pM and favorable pharmacokinetics and off-target activity profile. Molecular dynamics comparison of 16 and its corresponding riboside 8 suggested a qualitative entropic advantage of 16 in hAAR binding. The 5-F substitution tended to increase hAAR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist 4 was shown to interact potently exclusively with AAR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for AAR agonists, which have translational potential for chronic disease treatment.
CiteXplore: 33062176