Table 2. Structural requirements of the binding pocket can guide scaffold-hopping. Pennington et al.47 showed that binding to a hydrophobic pocket called for the incorporation of a fluoropyridine rather than a similarly stable pyrimidine. RLM: rat liver microsomes.

Entry	Compound	X	Y	RLM Clint (μL min–1 mg–1)	clog P
1	6a	N	CH	130	3.1
2	6b	CH	N	67	3.1
3	6c	N	N	28	2.3
4	6d	CF	N	26	3.2