Covalent Inhibitor Series

A series of compounds identified during our HTS featured small dipeptides with the C-terminus replaced by a heterocyclic ketone moiety as exemplified by compound 6. We were pleased to see the high activity of 6 (59 nM) and assumed that the activated ketone residue might act as a covalent-reversible inhibitor of CatA. 

6941 23 The Discovery of Cathepsin A Inhibitors A Project-Adapted Fragment Approach Based on NTS Results 

The ethyl group makes van der Waals contacts with Gly57 and Cys375 and is located next to the covalent link with SerlSO. The morpholino group does not 

Lipinski Rule-of-5 H-Donors 2 H-Accept. 10 clogP 2.72 MW 457.52 Violations 0 RotBonds 9 PSA 126.66A2 LLE 4.8 H-Donors 2 H-Accept. 7 ClogP 6.42 MW 540.44 Violations 2 RotBonds 7 PSA 93.45A2 LLE 2.55 LE 0.239 H-Donors 1 H-Accept. 8 clogP 4.64 MW 523.57 Violations 1 RotBonds 5 PSA 81.91A2 LLE 3.967 LE 0.221 

Our intended therapeutic application of CatA inhibitors is in the cardiovascular disease indication with a high likelihood of chronic treatment General considerations around bioavailability, long-term safety, and tolerability increased our preference for a different lead series. 

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Covalent Inhibitor Series Malonic acid series Pyrazolone series... 

Gehlhaar, D. K., Bouzida, D., and Rejto, P. A. (1999) Reduced dimensionality in ligand-protein structure prediction covalent inhibitors of serine proteases and design of site-directed combinatorial libraries. ACS Symposium Series 719, 292-311. 

The half-life of the a subunit has usually been inferred rather than directly measured. Thus, treatment of rats with cycloheximide resulted in a loss of ATPase activity with a half-life of 72 h [29]. Recovery from inhibition with the covalent inhibitor, omeprazole, showed a half-life of 30 h in the same series of experiments. Other workers have claimed a half-life of recovery from proton pump inhibition of as short as 15 h [30]. 

Another series of non-covalent competitive inhibitors reaching toward the F side has been reported by Boehringer Ingelheim researchers. Bailey, et al. [116]... 

Two laboratories have independently disclosed an interesting series of mechanism-based inhibitors. The dihydropyrrole 31, which appeared in a patent application [61], was reported to inhibit rat lung SSAO/VAP-1 with an IC50 = 500 nM. Recently, the Sayre team extended earlier work [74] and showed that these inhibitors, exemplified by 32, covalently bound to the enzyme with the cofactor in the reduced form [75]. Presumably, aromatization of the dihydropyrrole moiety accounts for the observed potencies. 

More recently, and based on the same concept, O Neill and coworkers have prepared a series of related systems (80a-c) based on Vennerstrom s adamantyl trioxolane unit". These derivatives, which are synthesized in only three steps from adamantan-2-one, have activity in the low nanomolar region (<3 nM versus K1 P. falciparum). Like the prototypes synthesized by the groups of Meunier" and Singh", these compounds can be formulated as water-soluble salts and it is anticipated that these agents may have the capacity to hit the parasite by two distinctive mechanisms. Indeed, any chemical or metabolic degradation of the endoperoxide bridge in these compounds will result in metabolites that may still have the ability to function as inhibitors of heme polymerization provided that they do not become covalently attached to proteins in the bioactivation process. 

Further studies in this compound series revealed that replacement of the ether oxygen with sulfur consistently gave inhibitors that behaved as class IV inhibitors. In each case covalent attachment to the enzyme thiol was detected by mass spec-... 

These extended-chain ketones are believed to interact with HLE similarity to the aldehyde and TFMK series of inhibitors. Although studies showing that they are true transition-state analogue inhibitors have not been reported, the formation of the covalent hemiketal adduct was documented in an X-ray crystallographic study of a DFK bound to PPE [150]. One notable finding is that the acidic N-terminal substituents first used by Trainor and co-workers to produce TFMKs with good in vivo profiles... 

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