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.
α-Diazo esters containing an amido group in the γ-position have been found to undergo a rhodium(II)-catalyzed transformation, producing five-membered ammonium or carbonyl ylides depending on the reaction
conditions used. In the absence of an external dipolarophile, ammonium ylides are the exclusive products
formed. In most cases these ylides cannot be isolated as they readily undergo sigmatropic rearrangement or
fragmentation reactions. In the presence of typical dipolarophiles such as DMAD or N-phenylmaleimide,
cycloaddition products derived from cyclic carbonyl ylide dipoles are formed as the major products. The rhodium
carbenoid intermediate generated in these reactions can either attack the lone pair of electrons on the amide
nitrogen (ammonium ylide formation) or the lone pair of electrons on the carbonyl oxygen (carbonyl ylide
formation). The experimental observations reflect a catalyst-promoted system of equilibria with a clear-cut
thermodynamic bias. To examine the underlying mechanism in detail, density functional theory (DFT)
calculations were performed on all plausible intermediates, including the full dirhodium tetracarboxylate
functionality. A semiquantitative energy manifold is developed that rationalizes the empirical observations
and provides a detailed picture of the role of the dirhodium(II) catalyst.
1-(Benzenesulfonyl-diazoacetyl)-pyrrolidin-2-one was prepared by a diazo transfer of 1-(benzenesulfonylacetyl)-pyrrolidin-2-one with p-acetamidobenzenesulfonyl azide and triethylamine. Treatment of the diazoimide with a catalytic quantity of rhodium(II) acetate resulted in the formation
of an isomünchnone dipole, which underwent bimolecular trapping with various dipolarophiles in
high yield. The initially formed cycloadducts were not isolable or observed, as they all readily
underwent ring opening to give the 3-hydroxy-2(1H)-pyridone ring system. The 3-hydroxy-2(1H)-pyridones were readily converted to the corresponding triflates, which function as suitable substrates
in various types of palladium-catalyzed cross-coupling reactions. Commercial tetrakis(triphenylphoshine)palladium was found to be a particularly effective catalyst for the cross-coupling with
aryl, vinyl, and acetylenic partners. An application of the method to the synthesis of the indolizidine
alkaloid (±)-ipalbidine was carried out in eight steps in 17% overall yield. The angiotensin-converting
enzyme inhibitor (−)-A58365A was also synthesized by a process based on the [3 + 2]-cycloaddition
reaction of a phenylsulfonyl substituted isomünchnone intermediate. The starting material for this
process was prepared from l-pyroglutamic acid and involved using a diazo phenylsulfonyl substituted
pyrrolidine imide. Treatment of the diazoimide with Rh2(OAc)4 in the presence of methyl vinyl
ketone afforded a 3-hydroxy-2-pyridone derivative, which was subsequently converted to the ACE
inhibitor in six additional steps.
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