Latha G. Nair

Substituted piperidines as hdm2 inhibitors

Novel small molecule HDM2 inhibitor, substituted piperidine, was identified. Initial SAR study indicated potential for several position optimizations. Additional potency enhancement was achieved by introducing a sidechain off the aromatic ring. DMPK study of one of the active compounds has shown a moderate oral PK and reasonable bioavailability.

P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.

SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1.

Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction.

The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.

Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors.

Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.