Chiral Pyrrolo[2,3-d]pyrimidine and Pyrimido[4,5-b]indole Derivatives:  Structure−Activity Relationships of Potent, Highly Stereoselective A₁-Adenosine Receptor Antagonists^,

Abstract

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 A2a. 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 A2aAR (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 nonxanthine A1AR antagonists known to date (Ki = 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]pyrimidin e (DPEAP, 17a) showed a Ki 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.

Bioisosterism, enantioselectivity, and molecular modeling of new effective N6‐ and/or N(9)‐substituted 2‐phenyl adenines and 8‐aza analogs: Different binding modes to A1 adenosine receptors

“…this article and the four taken from the literature (R and S ADPEP [Muller et al, 1990] and R and S DPEAP [Muller et al, 1996]) are shown in Table 3. They were selected for the molecular modeling study because the six pairs of enantiomers considered bear the chiral substituent, respectively, at positions corresponding to N 6 and N(9) of the adenine nucleus.…”

“…The hypothesis that some antagonists of the A 1 adenosine receptors may arrange themselves in the binding site according to different orientations has been suggested by other groups with regard to xanthine derivatives [Dooley et al, 1992;Dudley et al, 1993]. A more recent article concerning a class of chiral ligands characterized by quite a high molecular diversity also suggests different possibilities of arrangement of these ligands in the binding site [Muller et al, 1996].…”

“…Among them, the most stereoselective compounds were 9-(1-phenyl)ethyl-2-phenyl-7,8-dimethyl-7-deazaadenine (ADPEP), ER = 35, [Muller et al, 1990] and 1-phenyl-ethyl-2-phenyl-4-aminopyrimido [4,5-b]indole (DPEAP), ER = 96 [Muller et al, 1996]. The enantioselectivity was attributed to the pocket facing the N 6 of adenosine also for these antagonists [Muller et al, 1996;Peet et al, 1990]. In these studies it was also evidenced, with regard to the group in the 2-position, that unsubstituted phenyl conferred the best affinity to the molecules; analogous results had previously been obtained on 2-aryl-8-azaadenines [Biagi et al, 1991].…”

“…These findings can confirm the similarity of binding mode between 2-phenyl substituted 7-deazaadenines and 2-phenyl substituted 8-azaadenines or adenines. Furthermore, the low stereoselectivity of the receptor lipophilic pocket in front of the N(9) position of adenosine was demonstrated by low affinity and stereoselectivity of N 6 -cyclopentyl-9-(1-phenylethyl)amino or 9-(1-phenylethyl)amino adenines [Thomson et al, 1992] and of N 4 ,7-bis(1-phenylethyl)-5,6-dimethyl-7H-pyrrolo[2, 3-d]pyrimidines [Muller et al, 1996].…”

Non‐Xanthine Antagonists for the Adenosine A1 Receptor

“…This compound had very little selectivity over the A 2A receptor [79]. Later work showed the 4-NH 2 group (i.e., 107) to be favourable, with the inclusion of an aromatic substituent at C(2) and a chiral moiety at N(9) [80].…”