Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors
Journal Article
·
· Journal of Medicinal Chemistry
- Bristol-Myers Squibb Research & Development, Pennington, NJ (United States)
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. Here, 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.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1347770
- Journal Information:
- Journal of Medicinal Chemistry, Vol. 58, Issue 15; ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Cited by: 25 works
Citation information provided by
Web of Science
Web of Science
Similar Records
Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles
Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors
The M358R variant of α{sub 1}-proteinase inhibitor inhibits coagulation factor VIIa
Journal Article
·
Mon Jun 30 00:00:00 EDT 2008
· J. Med. Chem.
·
OSTI ID:1347770
+11 more
Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors
Journal Article
·
Sat Oct 01 00:00:00 EDT 2016
· Bioorganic & Medicinal Chemistry Letters
·
OSTI ID:1347770
+11 more
The M358R variant of α{sub 1}-proteinase inhibitor inhibits coagulation factor VIIa
Journal Article
·
Fri Feb 12 00:00:00 EST 2016
· Biochemical and Biophysical Research Communications
·
OSTI ID:1347770