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Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H2 Receptor Agonists†
ACS Omega ( IF 4.1 ) Pub Date : 2018-03-09 00:00:00 , DOI: 10.1021/acsomega.8b00128
Steffen Pockes 1 , David Wifling 1 , Max Keller 1 , Armin Buschauer 1 , Sigurd Elz 1
Affiliation  

On the basis of the long-known prototypic pharmacophore 3-(1H-imidazol-4-yl)propylguanidine (SK&F 91486, 2), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H2 receptor (H2R) agonists with various alkyl spacers were synthesized. Aiming at increased H2R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h/gp/rH2R. The most potent analogue, the thiazole-type heterodimeric ligand 63 (UR-Po461), was a partial agonist (Emax = 88%) and 250 times more potent than histamine (pEC50: 8.56 vs 6.16, gpH2R, atrium). The homodimeric structures 56 (UR-Po395) and 58 (UR-Po448) exhibited the highest hH2R affinities (pKi: 7.47, 7.33) in binding studies. Dimeric amino(methyl)thiazole derivatives, such as 58, generated an increased hH2R selectivity compared to the monomeric analogues, e.g., 139 (UR-Po444). Although monomeric ligands showed up lower affinities and potencies at the H2R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine hH4R ligands.

中文翻译:

高强度,稳定和选择性的二聚杂芳基丙基胍型组胺H 2受体激动剂

在长已知的原型药效3-(1的基础ħ -咪唑-4-基)propylguanidine(SK&F 91486,2),单体,同型二聚体,和异源二聚体bisalkylguanidine型组织胺H 2 2受体(H 2 R)激动剂与合成了各种烷基间隔基。为了提高配体的H 2 R选择性,根据生物立体异构体,将咪唑-4-基部分替换为咪唑-1-基,2-氨基噻唑-5-基或2-氨基-4-甲基噻唑-5-基。方法。事实证明,所有化合物在h / gp / r H 2 R均为部分或全部激动剂。最有效的类似物,噻唑型异二聚体配体63(UR-Po461)是部分激动剂(E max = 88%),效力是组胺的250倍(pEC 50:8.56 vs 6.16,gp H 2 R,心房)。在结合研究中,同型二聚体结构56(UR-Po395)和58(UR-Po448)表现出最高的h H 2 R亲和力(p K i:7.47、7.33)。与单体类似物(例如139)相比,二聚氨基(甲基)噻唑衍生物(例如58)产生了更高的h H 2 R选择性(UR-Po444)。虽然单体的配体出现了较低的亲和力和效力在H 2 R,具有短由烷基侧链类化合物129(UR-Po194)被证明是高度仿射ħ ħ 4 - [R配体。
更新日期:2018-03-09
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