title: Atropisomer Control in Macrocyclic Factor VIIa Inhibitors.
abstract: Incorporation of a methyl group onto a macrocyclic FVIIa inhibitor improves potency 10-fold but is accompanied by atropisomerism due to restricted bond rotation in the macrocyclic structure, as demonstrated by NMR studies. We designed a conformational constraint favoring the desired atropisomer in which this methyl group interacts with the S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint was prepared and demonstrated by NMR to reside predominantly in the desired conformation. This modification improved potency 180-fold relative to the unsubstituted, racemic macrocycle and improved selectivity. An X-ray crystal structure of a closely related analogue in the FVIIa active site was obtained and matches the NMR and modeled conformations, confirming that this conformational constraint does indeed direct the methyl group into the S2 pocket as designed. The resulting rationally designed, conformationally stable template enables further optimization of these macrocyclic inhibitors.
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Glunz
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mueller
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ladziata
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Wurtz
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Bristol-Myers Squibb Research & Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
mesh_terms: D018360:Crystallography, X-Ray; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047028:Macrocyclic Compounds; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa