{"doi":"10.1111/cbdd.14039","title":"2‐Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon‐like peptide 1 receptor","abstract":"We report the discovery of two new 2-aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes. One of the chemotypes, (S-1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP-1R PAMs. When combined with GLP-1 peptide, S-1 increased the GLP-1R activity in a dose-dependent manner in a cell-based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S-1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293-CREB cell line. Insulin secretion studies found S-1 combined with GLP-1 increased insulin secretion by 1.5-fold at 5 μM. In a mechanistic study, evidence is provided that the synergistic effect of S-1 with GLP-1 may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2-aminothiophene derivatives are a new and promising class of GLP-1R PAMs.","journal":"Chemical Biology & Drug Design","year":2022,"id":284720,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":962938,"name":"James A. McKee","orcid":null,"position":1,"is_corresponding":false},{"id":962939,"name":"Phu Do","orcid":null,"position":2,"is_corresponding":false},{"id":962940,"name":"Jeffrey A. Campbell","orcid":null,"position":3,"is_corresponding":false},{"id":245657,"name":"Jian Ma","orcid":"0000-0002-4963-304X","position":4,"is_corresponding":false},{"id":962479,"name":"Zhiyu Li","orcid":"0000-0001-5837-0547","position":5,"is_corresponding":false},{"id":962480,"name":"Nicholas J. Miller","orcid":"0000-0001-9827-8286","position":7,"is_corresponding":false},{"id":962941,"name":"Chananchida Srikanlaya","orcid":null,"position":8,"is_corresponding":false},{"id":962481,"name":"Dianzheng Zhang","orcid":"0000-0001-7732-9689","position":9,"is_corresponding":false},{"id":245662,"name":"Xianxin Hua","orcid":"0000-0003-4862-4691","position":10,"is_corresponding":false},{"id":519383,"name":"Zhijun Li","orcid":"0000-0001-6326-5282","position":11,"is_corresponding":false},{"id":962937,"name":"Tejashree Redij","orcid":null,"position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T00:29:36.828109Z","pmid":"35313084","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}