1. Structure-Guided Design of Substituted Biphenyl Butanoic Acid Derivatives as Neprilysin Inhibitors
Toshio Kawanami, et al. ACS Med Chem Lett. 2020 Jan 27;11(2):188-194. doi: 10.1021/acsmedchemlett.9b00578. eCollection 2020 Feb 13.
Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1' that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable, and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found subsite in S1'. We report herein the discovery and preclinical profiling of compound 13, which paved the path to our clinical candidate.
2. Methods and Approaches for the Solid-Phase Synthesis of Peptide Alcohols
Fernando J Ferrer-Gago, Li Quan Koh Chempluschem. 2020 Apr;85(4):641-652. doi: 10.1002/cplu.201900749.
Many methods have been developed for attaching an alcohol functionality to a solid support. However, not all of these methods are used to obtain peptide alcohols. In this Minireview, we will discuss several of the most important methods and approaches for the synthesis of peptide alcohols and the attachment of hydroxy groups to a solid support for the synthesis of cyclic peptides. Some of the methods include the use of functionalized Wang resin and the attachment of an alcohol to an enol ether resin. We also discuss the use of the chlorotrityl resin, one of the most common linkers used to obtain peptide alcohols. In addition, we outline the recently developed resins with the Rink, Ramage and Sieber handles. The majority of these methods have been used to synthesize many important drugs, such as octreotide and the antibiotic peptaibols.
3. Functionalized Resins for the Synthesis of Peptide Alcohols
Fernando J Ferrer-Gago, Li Quan Koh, David P Lane Chemistry. 2020 Jan 7;26(2):379-383. doi: 10.1002/chem.201903965. Epub 2019 Nov 19.
Peptide alcohols are clinically important compounds that are underexplored in structure-activity relationship (SAR) studies in drug discovery. One reason for this underutilization is that current syntheses are laborious and time consuming. Herein, we describe the preparation and utility of Rink, Ramage, and Sieber-chloride resins, which enables the use of a general, easy and practical method for the attachment of fluorenylmethoxycarbonyl (Fmoc)-amino alcohols to a solid support, in the synthesis of peptide alcohols. This method is the first straightforward Fmoc/tBu synthesis of peptide alcohols starting from a pre-loaded resin. The synthesized peptide alcohols can be detached from the linkers through conventional methods. Treatment with trifluoroacetic acid (TFA) (95 %) and scavengers such as triisopropylsilane and water for 2 h is sufficient to obtain a fully deprotected peptide alcohol, while treatment with 20 % hexafluoroisopropanol in dichloromethane renders a fully protected peptide alcohol that can be further modified at the C-terminus. As examples, the new resins were used in straightforward, relatively rapid syntheses of the peptide alcohols octreotide, alamethicin, and a segment of trichogin GA IV, as well as the first synthesis of stapled peptide alcohols.
