A novel series of potent and selective hexokinase 2 (HK2) inhibitors, 2,6-disubstituted glucosamines, has been identified based on HTS hits, exemplified by compound 1. Inhibitor-bound crystal structures revealed that the HK2 enzyme could adopt an "induced-fit" conformation. The SAR study led to the identification of potent HK2 inhibitors, such as compound 34 with greater than 100-fold selectivity over HK1. Compound 25 inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via (13)CNMR measurement of [3-(13)C]lactate produced from [1,6-(13)C2]glucose added to the cell culture.

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The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K(i,app) = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.

A novel thiazolopyrimidinone series of PI3K-beta selective inhibitors has been identified. This chemotype has provided an excellent tool compound, 18, that showed potent growth inhibition in the PTEN-deficient breast cancer cell line MDA-MB-468 under anchorageindependent conditions, and it also demonstrated pharmacodynamic effects and efficacy in a PTENdeficient prostate cancer PC-3 xenograft mouse model. KEYWORDS: PI3K-beta inhibitor, PTEN-deficient, phosphatidylinositol 3-kinase, homology model, structure−activity relationship S ince 2006, numerous small molecule phosphatidylinositol 3-kinase (PI3K) inhibitors have entered a wide range of clinical trials, primarily as targeted anticancer agents. 1,2 These molecules are either class I pan-PI3K inhibitors (with or without mTOR activity) or PI3K-alpha selective or PI3K-delta selective inhibitors. Despite many years of effort, it remains unclear what PI3K target selectivity profile is required of an inhibitor to provide a safe and effective agent for a specific patient population. Recent preclinical studies have shown that, in a PTEN-loss context, tissue-specific deletion of the PI3K-beta isoform in the prostate specifically reduces PI3K signaling and blocks the formation of aggressive prostate tumors. 3 Driven by these intriguing data, a couple of academic groups have published their efforts on identifying novel beta-isoform selective small molecule tools or using an existing tool molecule to understand the biology and the pathway in depth. 4 In previous communications, 5 we have reported on the discovery of two novel series of PI3K-beta inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones and 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones, which are exemplified by compounds 1 and 2 (Figure 1). Although these are excellent tool molecules for understanding PI3K-beta biology at a cellular level, they are limited from in vivo target validation due to the poor rodent pharmacokinetic profile. 6 The modeling and SAR results from our two previous series have suggested that a potent and selective PI3K-beta inhibitor could be designed from a bicyclic core structure bearing substituents designed to make three key binding interactions: (a) a carbonyl group to interact with the back-pocket Tyr-839; (b) a morpholine to act as a hinge binder; and (c) a lipophilic group that can induce a selectivity-pocket formed by Met-779 and Trp-787 (Figure 2A). We soon discovered that thiazolopyrimidinones with a substituted benzyl group at the N1-position met the above requirements (Figure 1).

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.

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