Cathepsin K inhibitor

When the target enzyme is difficult to obtain, related enzymes could be used to provide insights in the design of novel ligands. For example, papain was used to design a class of potent cathepsin K inhibitors [33] spanning both sides of the papain active site. However, fine-tuning these inhibitors to produce more potent ones required the use of the crystal structure of cathepsin K itself [34],... 

LaLonde JM, Zhao B, Smith WW, Janson CA, DesJarlais RL, Tomaszek TA, Carr TJ, Thompson SK, Oh HJ, Yamashita DS, Veber DF, Abdel-Meguid SS. Use of papain as a model for the structure-based design of cathepsin K inhibitors crystal structures of two papain-inhibitor complexes demonstrate binding to S -subsites. J Med Chem 1998 41 4567-4576. 

The synthesis of the /V-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs I ruthenium catalyst. This azepine was an important precursor for the preparation, via epoxidation of the double bond, of a number of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors <06JMC1597>. 

Case study structure-based design of cathepsin K inhibitors... 

Figure 17.3 Schematic representation of the design of the symmetric cathepsin K inhibitor diacylaminomethyl ketone (1,3-bis[[A/-[(phenylmethoxy)carbonyl]-L-leucyl]amino]-2-propanone), based on the crystal structures of papain bound to leupeptin (Leu-Leu-Arg-aldehyde) and to Cbz-Leu-Leu-Leu-aldehyde, and an example of its further optimization.

Table 17.2 Structure-based enhancement of cathepsin k inhibitor s potency and selectivity...

Thompson et ah, 1998 Marquis et al., 1999). Once each half was optimized, more SBDD cycles were needed to tweak the full molecule. This work resulted in numerous potent and selective cathepsin K inhibitors an example is shown in Fig. 17.3. Improvements in potency and selectivity of the compounds shown in Fig. 17.3 are listed in Table 17.2. Much of this work was recently summarized in Veber and Cummings (2004). 

D. F. (1998). Stmcture-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic. /. Med. Chem. 41,3923-3927. 

Veber, D. F. and Cummings, M. D. (2004). Structure-based design of cathepsin K inhibitors. In Protein Crystallography in Drug Discovery. Methods and Principles in Medicinal Chemistry, Babine, R. E. and Abdel-Meguid, S. S., eds, Vol. 20, Wiley-VCH, p. 127-146. 

S. Leger, F. Masse, M.E. McGrath, D.J. McKay, M.D. Percival, D. Riendeau, S.B. Rodan, M. Therien, V.L. Truong, G. Wesolowski, R. Zambonia, W.C. Black, Identification of a potent and selective non-basic cathepsin K inhibitor, Bioorg. Med. Chem. Lett. 16 (2006) 1985-1989. 

A concise alternative synthesis of the azepinones 241 has been developed based on the key ring-closing metathesis of the a-amino enones 240 (Equation 34) <2006H(67)549>. The substrate concentration was 5 x 10 3M and yields of products are given in Table 4. The azepinone 241c was then converted to a known cathepsin K inhibitor. 

Top Four-dimensional library design [94] (left) utilized by SmithKIine Beecham for generating cathepsin K inhibitors (right). 

The structural information developed in this project and molecular modeling studies based thereon proved to be very valuable in guiding the medicinal chemistry effort directed toward the development of therapeutically useful cathepsin K inhibitors, as will be discussed here. Through this work it has also been possible to highlight some of the present limitations on the use of structural information, the recognition of which can serve to guide the advances necessary to make it even more productive in the future. 

The observation of two distinct active site binding directions had critical impact on the design of novel class II type inhibitors in the course of the SmithKline Beecham medicinal chemistry effort. Our long term strategy for developing improved cathepsin K inhibitors had been to increase inhibitor selectivity by using electrophilic groups of lower intrinsic chemical reactivity than the aldehydes. It... 

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