title: Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism.
abstract: We present a series of oxadiazolothiazinones, selective inotropic agents on isolated cardiac tissues, devoid of chronotropy and vasorelaxant activity. Functional and binding data for the precursor of the series (compound 1) let us hypothesize LTCC blocking activity and the existence of a recognition site specific for this scaffold. We synthesized and tested 22 new derivatives: introducing a para-methoxyphenyl at C-8 led to compound 12 (EC50 = 0.022 μM), twice as potent as its para-bromo analogue (1). For 10 analogues, we extended the characterization of the biological properties by including the assessment of metabolic stability in human liver microsomes and cytochrome P450 inhibition potential. We observed that the methoxy group led to active compounds with low metabolic stability and high CYP inhibition, whereas the protective effect of bromine resulted in enhanced metabolic stability and reduced CYP inhibition. Thus, we identified two para-bromo benzothiazino-analogues as candidates for further studies.
authors.affiliation: Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia , Via Elce di Sotto 10, 06123 Perugia, Italy.|Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences , 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Severi
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences , 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences , 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.affiliation: Dipartimento di Neuroscienze, Area del Farmaco e Salute del Bambino (NEUROFARBA) , Viale Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Matucci
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Micucci
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.affiliation: Dipartimento di Chimica 'G. Ciamician', Alma Mater Studiorum-Università di Bologna , Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D013843:Thiazines; D014665:Vasodilator Agents; D003577:Cytochrome P-450 Enzyme System