title: Synthesis, biological evaluation, and three-dimensional quantitative structure-activity relationship study of small-molecule positive modulators of adrenomedullin.
abstract: Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of several diseases such as hypertension, cancer, diabetes, and renal disorders, becoming an interesting new target for the development of drugs. In a recent high-throughput screening study, a positive modulator with a bistriazole structure has been identified.(1) In this work, a new series of structurally related compounds has been synthesized by reaction of phenoxyacetic acid with the corresponding dihydrazide, followed by treatment of the formed bisoxadiazoles with benzylamine. The affinity toward AM of the lead compound, and a structurally related family obtained from the small-molecule NCI library together with the synthesized series, has been determined. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study and conformational and molecular dynamics simulations have shown that the presence of a free NH and a phenyl group is essential for the interaction of these compounds with AM.
authors.affiliation: Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, Madrid, Spain.
authors.forename: Mario A
authors.initials: MA
authors.lastname: García
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Martín-Santamaría
authors.forename: Mónica
authors.initials: M
authors.lastname: Cacho
authors.forename: Fernando Moreno
authors.initials: FM
authors.lastname: de la Llave
authors.forename: Miguel
authors.initials: M
authors.lastname: Julián
authors.forename: Alfredo
authors.initials: A
authors.lastname: Martínez
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Pascual-Teresa
authors.forename: Ana
authors.initials: A
authors.lastname: Ramos
mesh_terms: D053607:Adrenomedullin; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D010455:Peptides / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D009281:Naphthalenes; D010455:Peptides; D014230:Triazoles; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide