Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability

Autor:	Qian Xiang, Dietmar A. Seiffert, Wu Yang, Tianan Fang, Joseph E. Myers, Joanne M. Smallheer, Patrick Y.S. Lam, Jeon Yoon T, Zhen Lou, Joanna Zheng, Joseph M. Luettgen, Jeffrey M. Bozarth, Steven Sheriff, Yufeng Wang, William R. Ewing, Zilun Hu, Indawati De Lucca, Donald J. P. Pinto, Michael J. Orwat, James R. Corte, Charles G. Clark, Karen A. Rossi, Alan R. Rendina, Timothy W. Harper, Ruth R. Wexler, David S. Nirschl, Baomin Xin, Yiming Wu
Rok vydání:	2019
Předmět:	Models Molecular Macrocyclic Compounds Serine Proteinase Inhibitors Clinical Biochemistry Administration Oral Biological Availability Pharmaceutical Science Factor XIa Ligands 01 natural sciences Biochemistry Structure-Activity Relationship Drug Discovery Hydrolase Humans Moiety Molecular Biology Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Ligand (biochemistry) Combinatorial chemistry Enhanced bioavailability 0104 chemical sciences Bioavailability 010404 medicinal & biomolecular chemistry Drug Design Molecular Medicine Structure based Linker
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 29:126604
ISSN:	0960-894X
Popis:	This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f2efb9337fd87b82e6dbe509f35d0ce6 https://doi.org/10.1016/j.bmcl.2019.08.008 Zobrazit plný text záznamu Full Text from ScienceDirect