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Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.

Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The amyloid hypothesis asserts thatexcess production or reducedclearance of the amyloid-β (Aβ) peptides in the braininitiates a sequence of events that ultimately lead to Alzheimer’sdisease and dementia. The Aβ hypothesis has identified BACE1as a therapeutic target to treat Alzheimer’s and led to medicinalchemistry efforts to design its inhibitors both in the pharmaceuticalindustry and in academia. This review summarizes two distinct categoriesof inhibitors designed based on conformational states of “closed”and “open” forms of the enzyme. In each category theinhibitors are classified based on the core catalytic interactiongroup or the aspartyl binding motif (ABM). This review covers thedescription of inhibitors in each ABM class with X-ray crystal structuresof key compounds, their binding modes, related structure–activitydata highlighting potency advances, and additional properties suchas selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamicdata. [ABSTRACT FROM AUTHOR]