Target Family-directed Masterkey Concept

The resulting sulfotransferase inhibitors together with their inhibitory activities are shown at the bottom. 

The protein superfamily of proteases [78, 79], however, is an ideal framework for a directed privileged structure-based masterkey concept. It has already been reported that the 5,5-trans-fused lactam moiety was systematically optimized and explored as a serine protease-directed scaffold by GlaxoSmithKline and has delivered progressible lead compounds for various members of that target class [3], such as thrombin [80, 81], elastase [82, 83], HCMV protease [84, 85], and the hepatitis C virus-encoded NS3-4A protease [86, 87]. Here, the initially identified scaffold was engineered toward the serine protease-wide commonality in substrate binding and processing [3], 

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

Middle Three dimensional library design (left) employed by the Ellman group [95] to generate viable protease inhibitors (right). 

Bottom The active site-spanning cyclohexanone core (left) was conceptually derived from a non-active site-spanning mono-substituted heterocyclohexanone derivative [96-98] (right). 

---