BACE1 is a key protease controlling the formation of amyloid ␤, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academiaandindustry.Herein,wereportthenonclinicalandearlyclinicaldevelopmentofLY2886721,aBACE1activesiteinhibitorthatreached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ␤ lowering in nonclinical animal models. Similar potent and persistent amyloid ␤ lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Protein kinase C (PKC) is a family of closely related serine and threonine kinases. Overactivation of some PKC isozymes has been postulated to occur in several diseases states, including diabetic complications. Selective inhibition of overactivated PKC isozymes may offer a unique therapeutic approach to disease states such as diabetic retinopathy. A novel series of 14-membered macrocycles containing a N-N'-bridged bisindolylmaleimide moiety is described. A panel of eight cloned human PKC isozymes (alpha, beta I, beta II, gamma, delta, epsilon, sigma, eta) was used to identify the series and optimize the structure and associated activity relationship. The dimethylamine analogue LY333531 (1), (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene++ +-1,3(2H)-dione, inhibits the PKC beta I (IC50 = 4.7 nM) and PKC beta II (IC50 = 5.9 nM) isozymes and was 76- and 61-fold selective for inhibition of PKC beta I and PKC beta II in comparison to PKC alpha, respectively. The additional analogues described in the series are also selective inhibitors of PKC beta. LY333531 (1) exhibits ATP dependent competitive inhibition of PKC beta I and is selective for PKC in comparison to other ATP dependent kinases (protein kinase A, calcium calmodulin, caesin kinase, src tyrosine kinase). The cellular activity of the series was assessed using bovine retinal capillary endothelial cells. Retinal endothelial cell dysfunction has been implicated in the development of diabetic retinopathy. Plasminogen activator activity stimulated by a phorbol ester (4 beta-phorbol 12,13-dibutyrate) in endothelial cells was inhibited by the compounds in the series with ED50 values ranging from 7.5 to 0.21 microM. A comparison of the PKC isozyme and related ATP dependent kinase inhibition profiles is provided for the series and compared to the profile for staurosporine, a nonselective PKC inhibitor. The cellular activity of the series is compared with that of the kinase inhibitor staurosporine.

Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl(3)-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl(3)-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethylterephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH(2)OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.

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