Structure-activity relationships of adenosines with heterocyclic N6-substituents.

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M. Aumann, Kylee
Ashton, T.
Baker, Stephen P.
H. Schiesser, Carl
J. Scammells, Peter
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D.L. Boger

Date
2007
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Abstract

Two series of N6-substituted adenosines with monocyclic and bicyclic N 6 substituents contg. a heteroatom were synthesized in good yields. These derivs. were assessed for their affinity ([3H]CPX), potency, and intrinsic activity (cAMP accumulation) at the A1 adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, resp.) were found to possess similar activities, whereas the corresponding selenium analog 27 was found to be more potent. A series of nitrogen contg. analogs showed varying properties, N6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the A1AR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N6-position was explored. N6-(7-Azabicyclo[2.2.1]heptan-2-yl)adenosine (38) proved to be a reasonably potent A1 agonist (Ki = 51 nM, IC50 = 35 nM) while further substitution on the 7''-nitrogen with tert-butoxycarbonyl (31, IC50 = 2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC50 = 9.0 nM) gave highly potent A1AR agonists.

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Bioorganic & Medicinal Chemistry Letters

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17

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24

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Medicinal and Biomolecular Chemistry

Organic Chemistry

Pharmacology and Pharmaceutical Sciences

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