Substituted pyrazoles as novel sEH antagonist: investigation of key binding interactions within the catalytic domain.

A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.

Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design.

Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.

Structure-based optimization of arylamides as inhibitors of soluble epoxide hydrolase.

Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.

Influence of the beta-alkoxy group on the diastereoselectivity of Aldol reactions of tetrahydro-4H-thiopyran-4-one with 4-Alkoxytetrahydro-2H-thiopyran-3-carboxaldehydes.

The diastereoselectivity of the aldol reaction of tetrahydro-4H-thiopyran-4-one (3) with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (9a) under a variety of conditions is examined. Under optimized conditions, three of the four possible diastereomers from this aldol reaction can be obtained selectively (3-16:1). Reactions of 9a with the Li, B, Mg(II), and Ti(IV) enolates of 3 and with the corresponding trimethylsilyl enol ether 4b in the presence of BF(3) x OEt(2), SnCl(4), or TiCl(4) as promoters gave the Felkin adducts exclusively (>95%) as mixtures of syn (11a) and anti (12a) diastereomers. Use of the "amine-free" Li enolate of 3 gave 12a with a much higher diastereoselectivity (9:1) and yield (70%) than that obtained using the lithium diisopropylamide-generated Li enolate of 3 (2-3:1; 15-40%). The TiCl(4)-promoted reaction of 4b with 9a gave 11a with excellent selectivity (16:1). In contrast, the MgBr(2) x OEt(2)-promoted reaction of 4b with 9a gave the anti-Felkin adducts exclusively as a 3:1 mixture of syn (13a)/anti (14a) diastereomers. Similar aldol reactions of 3 with the cis and trans isomers of 4-(methoxy)methoxytetrahydro-2H-thiopyran-3-carboxaldehyde (9b and 9c) were examined to probe the influence of the ketal protecting group in 9a on the observed aldol diastereoselectivity. The results are rationalized by applying Evans' stereochemical model for merged 1,2- and 1,3-asymmetric induction (non-chelation), with the exception of the MgBr(2) x OEt(2)-promoted reactions of 4b with 9a, 9b, and 9c, which are accommodated by assuming chelation control. Comparison of the reactions of 9a, 9b, and 9c suggests that the ketal group in 9a uniquely allows high levels of either Felkin or anti-Felkin selectivity to be achieved.