title: Statistical molecular design, parallel synthesis, and biological evaluation of a library of thrombin inhibitors.
abstract: A library of thrombin inhibitors has been designed using statistical molecular design. An aromatic scaffold was used, with three varied positions corresponding to three pockets at the active site of thrombin (the S-, P-, and D-pockets). The selection was performed in the building block space, and previously acquired data were included in the design procedure. The design resulted in six, four, and six building blocks for the first (S), second (P), and third (D) pockets, respectively. A second round of selection applied to the combined selected building blocks resulted in a subset of 18 compounds. The selected library was synthesized in parallel and biologically evaluated. The compounds were analyzed with respect to their inhibition (pIC(50)) of thrombin; membrane permeability, estimated by migration behavior in micellar media (CE log k') and pK(a); and specificity with respect to inhibition (K(i)) of trypsin. Multivariate QSAR studies of the responses yielded valuable results and information that could only be found using statistical molecular design in combination with multivariate analysis.
authors.affiliation: AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. anna.linusson@astrazeneca.com
authors.forename: A
authors.initials: A
authors.lastname: Linusson
authors.forename: J
authors.initials: J
authors.lastname: Gottfries
authors.forename: T
authors.initials: T
authors.lastname: Olsson
authors.forename: E
authors.initials: E
authors.lastname: Ornskov
authors.forename: S
authors.initials: S
authors.lastname: Folestad
authors.forename: B
authors.initials: B
authors.lastname: Nordén
authors.forename: S
authors.initials: S
authors.lastname: Wold
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002417:Cattle; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D015842:Serine Proteinase Inhibitors; D013223:Statistics as Topic; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry
chemical_list: D001557:Benzenesulfonates; D015842:Serine Proteinase Inhibitors; D014357:Trypsin; D013917:Thrombin