Discovery and SAR Studies of Orally Active Somatostatin Receptor Subtype-2 (SSTR2) Agonists for the Treatment of Acromegaly
Discovery and SAR Studies of Orally Active Somatostatin Receptor Subtype-2 (SSTR2) Agonists for the Treatment of Acromegaly
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DOI：
10.1021/acschemneuro.0c00124
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发表时间：
2020-05-20
影响因子：
5
通讯作者：
Imagawa, Akira
中科院分区：
文献类型：
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作者：
Ishida, Akiharu;Tajima, Yohei;Imagawa, Akira
肢端肥大症是一种由生长激素分泌过多引起的疾病。目前通过静脉注射激活生长抑素受体亚型2（SSTR 2）的环肽药物治疗。在此，从一种热门化合物中鉴定出新型非肽类、小分子和口服活性SSTR 2激动剂（13）。药效团研究使支架跳跃获得一个独特的3，4，5-三取代吡啶基序。进一步优化赋予了有效的SSTR 2激动活性和代谢稳定性。对几种化合物进行了评价，这些化合物在大鼠中显示出良好的口服药代动力学曲线，一种代表性化合物（25）显示出对大鼠中由生长激素释放激素诱导的生长激素分泌的高效抑制。基于这些结果，25被确定为进一步优化的有希望的先导化合物。还描述了该化合物的构效关系（SAR）研究和代谢稳定性数据。
Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound (13). Pharmacophore studies enabled scaffold hopping to obtain a unique 3,4,5-trisubstituted pyridine motif. Further optimization conferred potent SSTR2 agonistic activity and metabolic stability. Several compounds were evaluated and these showed good oral pharmacokinetic profiles in rats, and one representative compound (25) showed highly potent inhibition of growth hormone secretion induced by growth hormone-releasing hormone in rats. Based on these results, 25 was identified as a promising lead for further optimization. A structure-activity relationship (SAR) study and the metabolic stability data for this compound are also described.