Discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridines as potent and selective SST5 agonists for the treatment of congenital hyperinsulinism

Zhao, Jian; Wang, Shimiao; Kim, Sun Hee; Han, Sangdon; Rico-Bautista, Elizabeth; Sturchler, Emmanuel; Nguyen, Julie; Tan, Hannah; Staley, Christine; Kusnetzow, Ana Karin; Betz, Stephen F.; Johns, Michael; Goulet, Lance; Luo, Rosa; Fowler, Melissa; Athanacio, Jon; Markison, Stacy; Struthers, R. Scott; Zhu, Yunfei

doi:10.1016/j.bmcl.2022.128807

Cited by 2 publications

(7 citation statements)

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“…It shows 15-, 100-, 1200-, and >2700-fold less activity at the SST4, SST3, SST2, and SST1 receptors, respectively ( Fig. 1 and Table 1 and ( 31 )). CRN02481 exhibits a similar selectivity profile at the murine SST receptors, activating the mouse SST5 receptor with high potency (EC 50 = 0.041 nM) and possessing decreased activity at mouse SST2 (EC 50 = 320 nM) and SST3 receptors (EC 50 = 10 nM).…”

Section: Resultsmentioning

confidence: 97%

“…In contrast to SS14 peptide analogs, CRN02481 was designed to be very potent and selective for the human SST5 receptor ( 31 ). It shows 15-, 100-, 1200-, and >2700-fold less activity at the SST4, SST3, SST2, and SST1 receptors, respectively ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Selective nonpeptide agonists of somatostatin receptors are the next evolution of somatostatin-related treatment for HI, which allows for more specific SST receptor selectivity and, importantly, the ability to be dosed orally. Our characterization of CRN02481, an SST5 selective nonpeptide agonist, discovered after a medicinal chemistry campaign aimed to find SST5 agonists ( 31 ), has clearly demonstrated its ability to significantly decrease insulin secretion similar to SS14 and its analogs and to be more potent and effective than diazoxide in suppressing tolbutamide-stimulated insulin secretion in healthy human islets. CRN02481 also prevents fasting hypoglycemia in an in vivo model of K ATP -HI and more importantly it exhibited anti-secretory effects on insulin in islets from HI patients.…”

Section: Discussionmentioning

confidence: 99%

“…Crinetics Pharmaceuticals launched a medicinal chemistry campaign aimed to discover selective nonpeptide SST5 agonists as a new approach to managing hyperinsulinemic hypoglycemia. Those efforts lead to the discovery of CRN02481 (also known as compound 28), a very specific and potent SST5 agonist with good drug-like properties ( 31 ). Here we describe the evaluation of CRN02481 on insulin secretion particularly in the context of HI.…”

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confidence: 99%

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A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

Juliana¹,

Chai²,

Arroyo³

et al. 2023

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

Juliana¹,

Chai²,

Arroyo³

et al. 2023

Journal of Biological Chemistry

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“…An allosteric inhibitor of the insulin receptor (RZ358) resulted in a statistically and clinically significant reduction of time spent in hypoglycemia [35]. Phase 2 studies of a long-acting glucagon analog (HM15136) and preclinical studies of a selective nonpeptide somatostatin receptor 5 agonist are currently underway [36,37].…”

Section: Managementmentioning

confidence: 99%

Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism

Rosenfeld

León

2023

Current Opinion in Pediatrics

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Purpose of review To highlight advances in congenital hyperinsulinism (HI), including newly described molecular mechanisms of disease, novel therapeutic interventions, and improved understanding of long-term outcomes. Recent findings Important advances have been made elucidating the molecular mechanisms responsible for HI. Non-coding variants in HK1 have been found to cause aberrant hexokinase expression. Inactivating mutations in SLC25A36 have been identified in children with features of the hyperinsulinism hyperammonemia syndrome. Low-level mosaic mutations in known HI genes have been detected in cases of ‘genetic testing negative’ HI. Identification and localization of focal HI lesions remains a priority, since focal HI can be cured with surgery. Use of 68Ga-NODAGA-exendin-4 PET has been proposed to localize focal lesions. Additional studies are needed before this technique replaces 18F-DOPA PET as standard of care. Treatment options for children with diffuse HI remain limited. The long-acting somatostatin analog, lanreotide, was shown to significantly improve glycemic control in a large series of children with HI. New therapies are under development, with promising preliminary results. Long-term quality of life and neurodevelopmental outcomes remain suboptimal. Summary Advanced genetic and epigenomic analytic techniques have uncovered novel molecular mechanisms of HI. Development of new drugs holds promise to improve long-term outcomes for individuals with HI.

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Discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridines as potent and selective SST5 agonists for the treatment of congenital hyperinsulinism

Cited by 2 publications

References 27 publications

A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism

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