title: 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.
authors.affiliation: Julius-Maximilians-Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische Chemie, Würzburg, Germany.
authors.forename: C E
authors.initials: CE
authors.lastname: Müller
authors.forename: U
authors.initials: U
authors.lastname: Geis
authors.forename: B
authors.initials: B
authors.lastname: Grahner
authors.forename: W
authors.initials: W
authors.lastname: Lanzner
authors.forename: K
authors.initials: K
authors.lastname: Eger
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003196:Computer Graphics; D003342:Corpus Striatum / Q000378:metabolism; D007042:Hypoxanthines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007042:Hypoxanthines; D007211:Indoles; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D018047:Receptors, Purinergic P1; D000225:Adenine