Synthesis, biological evaluation, and three-dimensional quantitative structure-activity relationship study of small-molecule positive modulators of adrenomedullin.
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.
García
Mario A
MA
Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, Madrid, Spain.
Martín-Santamaría
Sonsoles
S
Cacho
Mónica
M
de la Llave
Fernando Moreno
FM
Julián
Miguel
M
Martínez
Alfredo
A
de Pascual-Teresa
Beatriz
B
Ramos
Ana
A
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
D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D009281:Naphthalenes; D010455:Peptides; D014230:Triazoles; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide