title: 1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists.
abstract: A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy. Electronic address: fabrizio.micheli@aptuit.com.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Micheli
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bernardelli
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Bianchi
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Braggio
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Castelletti
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Palmina
authors.initials: P
authors.lastname: Cavallini
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavanni
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Cremonesi
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Dal Cin
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Feriani
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oliosi
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Semeraro
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Tarsi
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tomelleri
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wong
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Visentini
authors.affiliation: Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Zonzini
authors.affiliation: Indivior Inc, The Fairfax Building, 10710 Midlothian Turnpike, Suite 430, Richmond, VA 23235, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000612884:1,2,4-triazolyl octahydropyrrolo(2,3-b)pyrrole; D051638:Ether-A-Go-Go Potassium Channels; D011758:Pyrroles; D050637:Receptors, Dopamine D3; D014230:Triazoles
keywords: Addiction; Antagonist; DA D3 receptor; Dopamine; Neuroscience