TY - JOUR
T1 - Structure-activity relationships of adenosines with heterocyclic N6-substituents
AU - Ashton, Trent Damon
AU - Aumann, Kylee M
AU - Baker, Stephen P
AU - Schiesser, Carl Herbert
AU - Scammells, Peter John
PY - 2007
Y1 - 2007
N2 - Two series of N-6-substituted adenosines with monocyclic and bicyclic N-6 substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([H-3]CPX), potency, and intrinsic activity (cAMP accumulation) at the A, adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N-6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N-6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the AIAR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N-6-position was explored. N6- (7-Azabicyclo[2.2.1] heptan-2-yl)adeno sine (38) proved to be a reasonably potent A, agonist (K-i = 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 A(1)AR agonists. (c) 2007 Elsevier Ltd. All rights reserved.
AB - Two series of N-6-substituted adenosines with monocyclic and bicyclic N-6 substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([H-3]CPX), potency, and intrinsic activity (cAMP accumulation) at the A, adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N-6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N-6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the AIAR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N-6-position was explored. N6- (7-Azabicyclo[2.2.1] heptan-2-yl)adeno sine (38) proved to be a reasonably potent A, agonist (K-i = 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 A(1)AR agonists. (c) 2007 Elsevier Ltd. All rights reserved.
M3 - Article
SN - 0960-894X
VL - 17
SP - 6779
EP - 6784
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 24
ER -