Submission Details

Design Rationale:

Structural analogs for mapping structure-activity relationship.

Other Notes:

There are 4 structural analogs of ADA-UCB-6c2cb422-1 in this set of designs. The [Cl->Br] analog is included to to investigate potency differences between the two halogen substituents. The [Cl->C#C] is included because the ethynyl substituent is,effectively an 'elongated chloro' that can penetrate more deeply into the P2 pocket (alternatively think of it as like a nitrile but with a smaller desolvation penalty). I've also included two cyclic analogs. These had been designed for linking a 'reversible' warhead for targeting the catalytic cysteine. However, I believe that they are still potentially useful even if the 'reversible' warhead is not used because linking any sp3 carbon to the amide nitrogen is expected to 'flip' the amide geometry. One question that they are designed to address is which of the 5 and 6-membered rings better positions the P1 and P2 substituents (I currently favor the 6-membered ring). I am assuming that racemates would be synthesized for these compounds.