Optimization of a 2,4-diaminopyrimidine HTS hit using a combination of parallel synthesis and X-ray crystallography afforded lead compound 16 IC50 = 655 nM [73,74]. The 1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinoline moiety of 16 was shown to occupy the S3 and Ss3p pockets of renin. Using NMR techniques, small molecules that could bind to the S2 pocket were identified and linked to 16 to give 17 IC50 = 1 nM . Further synthesis lead to 18 IC50 = 1nM, %F = 8), 19 (IC50 = 48 nM, %F = 74) and 20 (IC50 = 2nM, %F = 34) [76,77].
20 R = NHCO2Me
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