Müller C E, Geis U, Grahner B, Lanzner W, Eger K
Julius-Maximilians-Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische Chemie, Würzburg, Germany.
J Med Chem. 1996 Jun 21;39(13):2482-91. 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 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.
已合成了一系列33种新型的、大多为手性的吡咯并[2,3 - d]嘧啶和嘧啶并[4,5 - b]吲哚衍生物，并在高亲和力腺苷受体（AR）亚型A1和A2a的放射性配体结合试验中进行了研究。这些化合物可被设想为在7位缺少氮的腺嘌呤和次黄嘌呤类似物（7 - 脱氮腺嘌呤和7 - 脱氮次黄嘌呤）。在AR上，7 - 脱氮腺嘌呤比7 - 脱氮次黄嘌呤的活性要强得多，对A1AR的亲和力处于低纳摩尔范围，对大鼠脑A1AR相对于A2aAR具有极高的选择性（数千倍），并且具有高立体选择性（高达96倍）。与吡咯并[2,3 - d]嘧啶相比，嘧啶并[4,5 - b]吲哚是更强效的A1AR拮抗剂。化合物34a（APEPI）是迄今为止已知的最有效和最具选择性的非黄嘌呤A1AR拮抗剂之一（Ki = 2.8 nM，A1选择性大于2000倍）。已鉴定出一类新型的非常强效的A1AR拮抗剂，即在外环氨基上带有取代基的2 - 苯基 - 7 - 脱氮腺嘌呤（N4 - 取代的吡咯并[2,3 - d]嘧啶）。(R)-N - (1 - 苯乙基)-4 - 氨基 - 5,6 - 二甲基 - 2 - 苯基 - 7H - 吡咯并[2,3 - d]嘧啶（DPEAP，17a）在A1AR上的Ki值为6.7 nM，A1选择性大于4000倍。基于两类化合物的空间、电子和疏水性质的比较，推测N4 - 取代的4 - 氨基吡咯并[2,3 - d]嘧啶（例如17a）和7 - 取代的衍生物（例如1a）具有不同的结合模式。已测定了所选化合物的水溶性和亲脂性。4 - 氨基 - 5,6 - 二甲基 - 2 - (3 - 氯苯基)-7H - 吡咯并[2,3 - d]嘧啶（4a）在本系列中显示出最高的水溶性/A1AR亲和力比，为368，A1选择性超过2000倍，立体选择性为64倍（R＞S）。因此，4a应该是用于体内评估的一个有趣的化合物。
