Synthesis of amino heterocycle aspartyl protease inhibitors

Abstract

Aspartyl proteases are important pharmacological targets. Historically aspartyl proteases have been commonly targeted with transition state derived peptidomimetics. The strategy to develop aspartyl protease inhibitors has undertaken a dramatic paradigm shift in the last 10 years. The pharmaceutical industry in 2005 disclosed several scaffolds or "head groups" that prompted the field to move beyond peptidomimetic derived inhibitors. Since the discovery of the first amino heterocycle aspartyl protease inhibitor, the amino hydantoin, industry and academia have positioned themselves for a foothold on the new molecular space, designing a variety of related "head groups". Both the design and synthetic efforts involved in constructing these scaffolds are varied and complex. Here we highlight the synthetic strategies used to access these amino heterocycle scaffolds.

Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362

“…A range of synthetic routes facilitating access to substituted cyclic guanidines has been described and reviewed Scheme describes the route used to access compounds 1 – 5 and UCB7362 .…”

“…A range of synthetic routes facilitating access to substituted cyclic guanidines has been described and reviewed. 30 Scheme 1 describes the route used to access compounds 1 – 5 and UCB7362 . The critical step involves a coupling-cyclization protocol of β amino ester 13 and a thiourea ( 8 or 9 ), which could be prepared from the corresponding amino THP ( 6 or 7 respectively).…”

Substrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity

“…[ 26 , 31 ] Both these tool compounds utilise head groups previously employed to target aspartyl proteases. WM382 ( 1 ) employs the imino pyrimidinone head group [32] originally used to target human beta‐secretase 1 (BACE1) and renin,[ 33 , 34 ] whereas 49c ( 2 ) utilizes the hydroxyethyl amine (HEA) scaffold, a substrate transition state mimetic previously exploited by inhibitors targeting HIV aspartyl protease [35] and Plasmodium plasmepsins. [ 30 , 36 , 37 ] In independent studies, WM382 ( 1 ) and 49c ( 2 ), were used as tool compounds to pharmacologically validate the role of PMIX in P. falciparum erythrocytic invasion, and the function of PMX in erythrocytic invasion and egress, in addition to critical events in transmission and liver stages of malaria.…”