Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1

• Published in: ACS medicinal chemistry letters Vol. 9; no. 7; pp. 736 - 740
• Main Authors: Kallander, Lara S., Washburn, David, Hilfiker, Mark A., Eidam, Hilary Schenck, Lawhorn, Brian G., Prendergast, Joanne, Fox, Ryan, Dowdell, Sarah, Manns, Sharada, Hoang, Tram, Zhao, Steve, Ye, Guosen, Hammond, Marlys, Holt, Dennis A., Roethke, Theresa, Hong, Xuan, Reid, Robert A., Gampe, Robert, Zhang, Hong, Diaz, Elsie, Rendina, Alan R., Quinn, Amy M., Willette, Bob
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.07.2018; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: 60 APPLIED LIFE SCIENCES; BMP-1; BMP1; Chemistry, Medicinal; fibrosis; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Letter; Life Sciences & Biomedicine; MMP12; PCP; Pharmacology & Pharmacy; Science & Technology; TLL1; TLL2; MMP12; BMP1; TLL2; TLL1; fibrosis; PCP; BMP-1; PROCOLLAGEN C-PROTEINASE
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.8b00173

Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug–drug interactions was managed by optimizing the series for subcutaneous injection.