{"entity": "researcher", "timestamp": "2026-07-14T04:00:10.956Z", "family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "affiliations": ["Science for Life Laboratory, Department of Medicinal Chemistry Uppsala University SE-751 23 Uppsala SWEDEN."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/011ee4a03a534099a5d71b0fdd6dbe81.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/011ee4a03a534099a5d71b0fdd6dbe81"}}, "publications": [{"entity": "publication", "iuid": "5036a5c3652d4398b7e088d828e8ce94", "links": {"self": {"href": "https://publications.scilifelab.se/publication/5036a5c3652d4398b7e088d828e8ce94.json"}, "display": {"href": "https://publications.scilifelab.se/publication/5036a5c3652d4398b7e088d828e8ce94"}}, "title": "Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-\u03b1]pyridines-Synthesis and Evaluation.", "authors": [{"family": "Engen", "given": "Karin", "initials": "K"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T"}, {"family": "Yadav", "given": "Anubha", "initials": "A"}, {"family": "Puthiyaparambath", "given": "Sharathna", "initials": "S"}, {"family": "Rosenstr\u00f6m", "given": "Ulrika", "initials": "U", "orcid": "0000-0002-0817-8140", "researcher": {"href": "https://publications.scilifelab.se/researcher/6cd5910fdd8c4f1b87d18223b11e3821.json"}}, {"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications.scilifelab.se/researcher/558a444faff84f108251e7521870ec2b.json"}}, {"family": "Jenmalm-Jensen", "given": "Annika", "initials": "A"}, {"family": "Hallberg", "given": "Mathias", "initials": "M"}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications.scilifelab.se/researcher/011ee4a03a534099a5d71b0fdd6dbe81.json"}}], "type": "journal article", "published": "2024-02-21", "journal": {"title": "Int J Mol Sci", "issn": "1422-0067", "volume": "25", "issue": "5", "issn-l": null}, "abstract": "Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 48 imidazo [1,5-\u03b1]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an IC50 value of 1.0 \u00b5M. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound's metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding.", "doi": "10.3390/ijms25052516", "pmid": "38473764", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC10931632"}, {"db": "pii", "key": "ijms25052516"}], "notes": [], "created": "2024-04-11T10:10:14.391Z", "modified": "2025-10-17T13:04:27.422Z"}, {"entity": "publication", "iuid": "1dc0cba1f4bc4a469774e55e3d8fe100", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1dc0cba1f4bc4a469774e55e3d8fe100.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1dc0cba1f4bc4a469774e55e3d8fe100"}}, "title": "Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors.", "authors": [{"family": "Engen", "given": "Karin", "initials": "K"}, {"family": "Vanga", "given": "Sudarsana Reddy", "initials": "SR"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Agalo", "given": "Faith", "initials": "F"}, {"family": "Konda", "given": "Vivek", "initials": "V"}, {"family": "Jensen", "given": "Annika Jenmalm", "initials": "AJ"}, {"family": "\u00c5qvist", "given": "Johan", "initials": "J", "orcid": "0000-0003-2091-0610", "researcher": {"href": "https://publications.scilifelab.se/researcher/9777a1c6e1bd4181bc46dce4be3c2146.json"}}, {"family": "Guti\u00e9rrez-de-Ter\u00e1n", "given": "Hugo", "initials": "H"}, {"family": "Hallberg", "given": "Mathias", "initials": "M"}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications.scilifelab.se/researcher/011ee4a03a534099a5d71b0fdd6dbe81.json"}}, {"family": "Rosenstr\u00f6m", "given": "Ulrika", "initials": "U", "orcid": "0000-0002-0817-8140", "researcher": {"href": "https://publications.scilifelab.se/researcher/6cd5910fdd8c4f1b87d18223b11e3821.json"}}], "type": "journal article", "published": "2020-03-00", "journal": {"volume": "9", "issn": "2191-1363", "issue": "3", "pages": "325-337", "title": "ChemistryOpen", "issn-l": "2191-1363"}, "abstract": "Insulin-regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non-peptide IRAP inhibitors derived from a spiro-oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)-promoted three-component reaction, or by a two-step one-pot procedure. For decoration of the oxindole ring system, rapid MW-assisted Suzuki-Miyaura cross-couplings (1 min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S-configuration of the spiro-oxindole dihydroquinazolinones accounts for the inhibition of IRAP.", "doi": "10.1002/open.201900344", "pmid": "32154052", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "OPEN201900344"}, {"db": "pmc", "key": "PMC7050655"}], "notes": [], "created": "2020-03-04T13:11:28.870Z", "modified": "2025-10-17T13:04:28.346Z"}, {"entity": "publication", "iuid": "8a54abdac0304e9eb0f0b3862fe27c80", "links": {"self": {"href": "https://publications.scilifelab.se/publication/8a54abdac0304e9eb0f0b3862fe27c80.json"}, "display": {"href": "https://publications.scilifelab.se/publication/8a54abdac0304e9eb0f0b3862fe27c80"}}, "title": "A Series of Analogues to the AT 2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode.", "authors": [{"family": "Isaksson", "given": "Rebecka", "initials": "R", "orcid": "0000-0002-6389-5046", "researcher": {"href": "https://publications.scilifelab.se/researcher/ecad4139af504c3aa65ac86c65de28bc.json"}}, {"family": "Lindman", "given": "Jens", "initials": "J", "orcid": "0000-0003-4795-6117", "researcher": {"href": "https://publications.scilifelab.se/researcher/595f3ad3a575491a95c76672c629c64b.json"}}, {"family": "Wannberg", "given": "Johan", "initials": "J", "orcid": "0000-0001-5494-0848", "researcher": {"href": "https://publications.scilifelab.se/researcher/d093f5fb52f644ce8994f3a6308272a8.json"}}, {"family": "Sallander", "given": "Jessica", "initials": "J", "orcid": "0000-0002-0408-5289", "researcher": {"href": "https://publications.scilifelab.se/researcher/ac374a149df9468d892e37bc11147a68.json"}}, {"family": "Backlund", "given": "Maria", "initials": "M", "orcid": "0000-0002-6253-816X", "researcher": {"href": "https://publications.scilifelab.se/researcher/bffc6d0b93b64dafa4c17abf7910964e.json"}}, {"family": "Baraldi", "given": "Dhaniel", "initials": "D", "orcid": "0000-0002-9688-4183", "researcher": {"href": "https://publications.scilifelab.se/researcher/226a2b7a6920494994ae795b95cf9381.json"}}, {"family": "Widdop", "given": "Robert", "initials": "R", "orcid": "0000-0002-6515-0435", "researcher": {"href": "https://publications.scilifelab.se/researcher/8a1c0488523f42ac9246798135cb57dd.json"}}, {"family": "Hallberg", "given": "Mathias", "initials": "M", "orcid": "0000-0002-9835-870X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6450e1c0206e41ec9aa59866bb529766.json"}}, {"family": "\u00c5qvist", "given": "Johan", "initials": "J", "orcid": "0000-0003-2091-0610", "researcher": {"href": "https://publications.scilifelab.se/researcher/9777a1c6e1bd4181bc46dce4be3c2146.json"}}, {"family": "Gutierrez de Teran", "given": "Hugo", "initials": "H", "orcid": "0000-0003-0459-3491", "researcher": {"href": "https://publications.scilifelab.se/researcher/b2c1a83f44474224b4788bfcbfcd1a43.json"}}, {"family": "Gising", "given": "Johan", "initials": "J", "orcid": "0000-0001-8852-6071", "researcher": {"href": "https://publications.scilifelab.se/researcher/558a444faff84f108251e7521870ec2b.json"}}, {"family": "Larhed", "given": "Mats", "initials": "M", "orcid": "0000-0001-6258-0635", "researcher": {"href": "https://publications.scilifelab.se/researcher/011ee4a03a534099a5d71b0fdd6dbe81.json"}}], "type": "journal article", "published": "2019-01-00", "journal": {"volume": "8", "issn": "2191-1363", "issue": "1", "pages": "114-125", "title": "ChemistryOpen", "issn-l": "2191-1363"}, "abstract": "We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT 2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R as compared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.", "doi": "10.1002/open.201800282", "pmid": "30697513", "labels": {"Drug Discovery and Development": "Collaborative"}, "xrefs": [{"db": "pii", "key": "OPEN201800282"}, {"db": "pmc", "key": "PMC6346239"}], "notes": [], "created": "2019-11-13T16:02:37.348Z", "modified": "2025-10-17T13:05:08.282Z"}]}