Chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives: Structure-activity relationships of potent, highly stereoselective A1- adenosine receptor antagonists

Article abstract of DOI:10.1021/jm960011w

A series of 33 novel, mostly chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives has been synthesized and investigated in radioligand binding assays at the high-affinity adenosine receptor (AR) subtypes A₁ and A(2a). The compounds can be envisaged as adenine and hypoxanthine analogs lacking the nitrogen in the 7-position (7-deazaadenines and 7-deazahypoxanthines). 7-Deazaadenines were much more potent than 7- deazahypoxanthines at AR with A₁AR affinities in the low-nanomolar range, extraordinarily high selectivity for the rat brain A₁AR versus the A(2a)AR (several thousandfold), and high stereoselectivity (up to 96-fold). Pyrimido[4,5-b]indoles were more potent A₁AR antagonists compared to pyrrolo[2,3-d]pyrimidines. Compound 34a (APEPI) is one of the most potent and most selective non-xanthine A₁AR antagonists known to date (K(i) = 2.8 nM, >2000-fold A₁-selective). A new class of very potent A₁AR antagonists has been identified, namely, 2-phenyl-7-deazaadenines bearing a substituent at the exocyclic amino group (N⁴-substituted pyrrolo[2,3-d]pyrimidines). (R)- N(1-Phenylethyl)-4-amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine (DPEAP, 17a) showed a K(i) value of 6.7 nM at A₁AR and >4000-fold A₁ selectivity. Different binding modes are postulated for the N⁴-substituted 4-aminopyrrolo[2,3-d]pyrimidines (e.g., 17a) and the 7-substituted derivatives (e.g., 1a), based on a comparison of steric, electronic, and hydrophobic properties of the two classes of compounds. Water solubility and lipophilicity have been determined for selected compounds. 4-Amino-5,6- dimethyl-2-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (4a) showed the highest water solubility/A₁AR affinity ratio of 368 in the present series, over 2000-fold A₁ selectivity, and 64-fold stereoselectivity (R > S). Therefore, 4a should be an interesting compound for in vivo evaluation.