Cholesterol gallstones are a gastrointestinal disease characterized by chronic, recurrent, high incidence rate (∼15%–20 %) and hidden symptoms [1,2]. Cholesterol gallstones can be asymptomatic or symptomatic, symptoms often precede the onset of potentially life-threatening complications of gallstones, such as acute cholecystitis, acute cholangitis and biliary pancreatitis. However, drugs that treat or prevent cholesterol gallstones are extremely limited, and only ursodeoxycholic acid (UDCA) has been employed as the first-line drug for the treatment of patients with normal gallbladder motor function [3]. Therefore, developing novel, effective, and oral small molecule drugs that can intervene cholesterol gallstones are urgently needed, as the cholesterol gallstones and complications seriously threaten human health and afford one of the highest socioeconomic costs in gastrointestinal diseases [4].

Somatostatin receptor subtype 5 (SSTR5) are G protein-coupled receptors that sense the somatostatin (SST) [[5], [6], [7]], and its highly distributed in the gastrointestinal tract, moderately distributed in pancreatic islets, and low distributed in the hypothalamus. When SSTR5 activated by SST or SST analogs, its biological effects are mainly to inhibits production or secretion of various hormones, such as insulin, glucagon (GCG), peptide YY (PYY), gastric inhibition polypeptide (GIP), glucagon-likepeptide-1 (GLP-1) and cholecystokinin (CCK) [6,7]. Insulin, GCG, PYY, GIP and GLP-1 are closely related to energy metabolism, and antagonizing SSTR5 has been demonstrated for the treatment of type 2 diabetes and obesity in previous studies [8,9]. Cholecystokinin (CCK) is an important neuro-intestinal peptide hormone produced by the enteroendocrine I-cells in the upper part of small intestine, and its mainly responsible for regulating intestinal cholesterol absorption, gallbladder contraction and emptying [10]. Notably, gallbladder emptying or gallbladder motor function is considered as an initial process in the pathogenesis of cholesterol gallstones [11], because the impaired gallbladder emptying causes prolonged stasis of lithogenic bile in the gallbladder, allowing more time and a permissive environment for bile crystallization and aggregation of that small crystal into macroscopic gallstones, and thus increase the risk of cholesterol gallstones, gallstone recurrence and cholangitis [12]. Therefore, SSTR5 activation leads to an inhibition of CCK secretion, which may be a potential risk for cholesterol gallstones. Clinical follow-ups also confirmed this, up to 50 % of the patients were treated chronically with the long-acting SST agonist developed gallstones [13,14]. Afterward, P. Kaczmarek et al. clearly demonstrated that SSTR5 activation inhibited egg yolk induced gallbladder emptying in a mice model [15]. Based on the above statement, SSTR5 activation is a tremendous risk for cholesterol gallstones, which provide a hint that antagonism of endogenous SST effects on SSTR5 might be a potential therapy for the treatment of cholesterol gallstones. Furthermore, SCOHIA PHARMA, Inc. researchers identified potential applications of the SSTR5 antagonist SCO-240 in the treatment of cholelithiasis and primary sclerotic cholangitis, and SCO-240 has entered a phase I clinical [16], but there are no detailed studies were disclosed, such as structure of SCO-240 and pharmacodynamic research process.

Considering the potential of SSTR5 antagonists to against cholesterol gallstones and the lack of relevant studies reported, we initialed our efforts to discover a novel SSTR5 antagonist and explored its effects on cholesterol gallstones. To date, only a few small molecule SSTR5 antagonists have been reported [[17], [18], [19], [20], [21], [22]]. Martin et al. reported the first seed structure of SSTR5 antagonists exhibiting micromolar potency—astemizole, fluspirilene, and loperamide (Fig. 1); and selected astemizole for further development to obtain the first small molecule SSTR5 antagonist [23]. After then, serval other small molecule SSTR5 antagonists charactered by the benzoic acid head group, the aromatic tail fragments and different core ring were reported [[17], [18], [19], [20], [21], [22]]. Here, we described the discovery and optimization of a series of SSTR5 antagonists using loperamide as a seed structure, and investigated its effects on cholesterol gallstones, hoping to provide a new perspective for the development of anti-gallstone drugs to address these unmet clinical needs.