SAR and Developability Optimization

This highlights the good feature map, but poor shape similarity for this compound. Without the benefit of stmctural information, it is difficult to know the relative importance of these attributes. 

This head group was also identified independently for this target, and the subsequent optimization of related compounds through to an in vivo tool is described in detail elsewhere [18, 19]. 

The overlay obtained for compound 123 shows a much better shape match to the template with an improved overlay of the aromatics in the bioisosteric head group. However, the acceptor features of the cyclic amide are less convincing, hence the lower rankings (Cresset rank 144 in both searches). The retrospective ROCS analysis ranked this exemplar 308th using the combo score (rank 96 by shape only and 840 by color), so this would have appeared much lower in the ROCS hits. The results summary shows that this monomer was not selected on the basis of the Cresset results but included as part of the additional chemists selection. This was due to the poor match of the FieldPoints around the head group with the reference compound. 

Compound 123 was subsequently taken forward for further investigation on the basis of its potency and developability profile. The compound showed low in vitro clearance in liver microsomes (Cli 0.8 (rat) and 1.1 (human) ml/min/g/tissue). 

An oral/intravenous pharmacokinetic study in rats indicated low clearance (21% liver blood flow), moderate volume of distribution, and good systemic exposure. The limited oral bioavailability and brain penetration observed in this study provided a platform for further optimization, with good molecular properties and a PSA below 70. However, a suitable compound from further development would require increased potency, solubility, and a clear hERG profile. 

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SAR and Developability Optimization 213 Table 12.2 Compounds exemplified with the Benzimidazole SAR exploration. 

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