ORGN 252 |
| Replacement of amide bonds with appropriate isosteres is an approach regularly explored in medicinal chemistry. Of all the amide replacements known, few functional groups are capable of preserving the hydrogen bond-donating properties observed with the amide. The trifluoroethylamino group is a functionality that exhibits this property in addition to improved metabolic stability over a peptide bond. Previous cathepsin K inhibitors have used basic P3 substituents to enhance potency and selectivity. The use of this trifluoroethylamino group to replace an amide bond was pivotal in the development of a new series of potent cathepsin K inhibitors. This modification resulted in increased potency and selectivity that allowed removal of a basic P3 substituent. The resulting non-basic inhibitor L-873724 is a 0.1 nM inhibitor of human cathepsin K with good selectivity towards the cathepsins B, L and S. L-873724 exhibits excellent pharmacokinetics and is potent in a primate model of osteoporosis. |
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Peptide Bond Isosteres
8:10 AM-12:00 PM, Monday, 11 September 2006 Moscone Center -- Room 135, Oral
Division of Organic Chemistry |