title: Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors.
abstract: On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1' alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa Ki = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC2x = 1.2 μM. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.forename: Indawati
authors.initials: I
authors.lastname: DeLucca
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047028:Macrocyclic Compounds; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa