A shortened interval between vaccinations with the trivalent inactivated influenza vaccine increases responsiveness in the aged.

We tested antibody responses to the trivalent inactivated influenza vaccine (TIV) in 34 aged individuals (>65 yrs) during the 2012/13 vaccination seasons. Nearly all had been vaccinated the previous year although the time interval between the two vaccine doses differed. One subgroup was re-vaccinated in 2012/13 within 6-9 months of their 2011/12 vaccination, the other received the two doses of vaccine in the typical ~12 month interval. Unexpectedly the sub-cohort with early revaccination exhibited significantly increased response rates and antibody titers to TIV compared to their normally re-vaccinated aged counter parts. Microarray analyses of gene expression in whole blood RNA taken at the day of the 2012/13 re-vaccination revealed statistically significant differences in expression of 754 genes between the individuals with early re-vaccination compared to subjects vaccinated in a normal 12 month interval. These observations suggest that TIV has long-lasting effects on the immune system affecting B cell responses as well as the transcriptome of peripheral blood mononuclear cells and this residual effect may augment vaccination response in patients where the effect of the previous vaccination has not yet diminished.

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11ß-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11ß-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.

Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition.

Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 µg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6h and bioavailability of 23%.

Synthesis of potent and orally efficacious 11ß-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016.

Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11ß-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11ß-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.

Comparative pharmacokinetics and metabolism studies in lean and diet- induced obese mice: an animal efficacy model for 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors.

Diet-induced obese (DIO) mice have been commonly used as an animal model in the efficacy assessment for new drug candidates. Although high-fat feeding has been reported to cause profound physiological changes, including the expression of drug-metabolizing enzymes, limited studies have been reported regarding the effect of obesity/diabetes on pharmacokinetics (PK) in animals. In this study, we investigated PK profiles of three 11 -HSD-1 inhibitors in the DIO mice and compared them to the normal lean mice. After oral administration, the in vivo exposure (AUC) of all three compounds was higher in DIO mice, which was consistent with the observed lower systemic clearance (CL) in DIO mice compared to lean mice. As illustrated by Compound E, a compound metabolized predominantly by CYP3A and 2C, the metabolic profiles for Compound E were qualitatively similar between DIO and lean mice, but quantitatively lower in the DIO mice. Indeed, P-450 activities for CYP3A and 2C as well as 2D were found to be lower in liver microsomes prepared from DIO mice. The calculated hepatic clearance (CLH) from in vitro studies with liver microsomes correlated well with the observed in vivo clearance for both DIO and lean mice. The calculated oral bioavailability (F%) based on intrinsic hepatic clearance (C(LH, int)) predicted ~3 fold increase in F% for the DIO mice, which was comparable to the observed value. Collectively, these data suggest that the higher F% is most likely due to the lower first-pass effect in DIO mice. This study highlights the needs to take caution when extrapolating PK and exposure data from healthy animals to diseased animals in designing pharmacological studies.

Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model.

Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

Benzhydrylquinazolinediones: novel cytosolic phospholipase A2alpha inhibitors with improved physicochemical properties.

The synthesis and optimization of a class of trisubstituted quinazoline-2,4(1H,3H)-dione cPLA(2)alpha inhibitors are described. Utilizing pharmacophores that were found to be important in our indole series, we discovered inhibitors with reduced lipophilicity and improved aqueous solubility. These compounds are active in whole blood assays, and cell-based assay results indicate that prevention of arachidonic acid release arises from selective cPLA(2)alpha inhibition.

Synthesis and biological evaluation of ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides: a class of potent aggrecanase-1 inhibitors.

The prevention of aggrecan (a key component of cartilage) cleavage via the inhibition of aggrecanase-1 may provide a unique opportunity to stop the progression of cartilage degradation in osteoarthritis. The evaluation of a series of biphenylsulfonamides resulted in the identification of the ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides analogs (19-21 and 24) with improved Agg-1 inhibition and MMP-2, MMP-13 activity.

Piperazine sulfonamides as potent, selective, and orally available 11beta-hydroxysteroid dehydrogenase type 1 inhibitors with efficacy in the rat cortisone-induced hyperinsulinemia model.

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11beta-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11beta-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.

beta-Keto sulfones as inhibitors of 11beta-hydroxysteroid dehydrogenase type I and the mechanism of action.

The design, synthesis, and biological evaluation of beta-keto sulfones as 11beta-HSD1 inhibitors and the mechanism of inhibition are described here. This class of compounds is not active against 11beta-HSD2 and therefore may have therapeutic potential for metabolic syndrome and type 2 diabetes.

Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors.

Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 microg/mL and has an oral bioavailability in rat of 35%.

Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.

Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated >50% inhibition of bovine cartilage degradation at 10 ng/mL.

Synthesis and SAR of highly selective MMP-13 inhibitors.

The structure-based design and synthesis of a series of novel biphenyl sulfonamide carboxylic acids as potent MMP-13 inhibitors with selectivity over MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-14, Aggrecanase 1, and TACE are described.

Synthesis and biological evaluation of sulfonamidooxazoles and beta-keto sulfones: selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I.

The design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeutic potential for metabolic syndrome, type 2 diabetes and related metabolic dysfunctions.

Structure-activity studies of a series of dipyrazolo[3,4-b:3',4'-d]pyridin-3-ones binding to the immune regulatory protein B7.1.

The interaction of co-stimulatory molecules on T cells with B7 molecules on antigen presenting cells plays an important role in the activation of naive T cells. Consequently, agents that disrupt these interactions should have applications in treatment of transplant rejection as well as autoimmune diseases. To this end, specific small molecule inhibitors of human B7.1 were identified and characterized. Herein, we report the identification of potent small molecule inhibitors of the B7.1-CD28 interaction. In a high-throughput screen we identified several leads that prevented the interaction of B7.1 with CD28 with activities in the nanomolar to low micromolar range. One of these, the dihydrodipyrazolopyridinone 1, was subsequently shown to bind the V-like domain of human B7.1 at equimolar stoichiometry. With this as a starting point, we report here the synthesis and initial in vitro structure-activity relationships of a series of these compounds.