- CYCLIC TETRAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS FOR THE TREATMENT OF METABOLIC DISORDERS
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The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R1, R1, R1, R1, R1, R1, R1, R1, R1, X1, X2, and X3 are described herein.
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Paragraph 0666; 0669; 0670
(2020/06/16)
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- Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects in Vivo
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Signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease which has recently been shown to play an important role in the development and function of antigen presenting cells such as B lymphocytes and dendritic cells. In this paper, we describe the discovery of the first selective and orally active SPPL2a inhibitor (S)-2-cyclopropyl-N1-((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1′-cyclopropan]-10-yl)-N4-(5-fluoro-2-methylpyridin-3-yl)succinamide 40 (SPL-707). This compound shows adequate selectivity against the closely related enzymes γ-secretase and SPP and a good pharmacokinetic profile in mouse and rat. Compound 40 significantly inhibited processing of the SPPL2a substrate CD74/p8 fragment in rodents at doses ≤10 mg/kg b.i.d. po. Oral dosing of 40 for 11 days at ≥10 mg/kg b.i.d. recapitulated the phenotype seen in Sppl2a knockout (ko) and ENU mutant mice (reduced number of specific B cells and myeloid dendritic cells). Thus, we believe that SPPL2a represents an interesting and druggable pharmacological target, potentially providing a novel approach for the treatment of autoimmune diseases by targeting B cells and dendritic cells.
- Velcicky, Juraj,Bodendorf, Ursula,Rigollier, Pascal,Epple, Robert,Beisner, Daniel R.,Guerini, Danilo,Smith, Philip,Liu, Bo,Feifel, Roland,Wipfli, Peter,Aichholz, Reiner,Couttet, Philippe,Dix, Ina,Widmer, Toni,Wen, Ben,Brandl, Trixi
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p. 865 - 880
(2018/02/17)
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- Oxazinanones as chiral auxiliaries: Synthesis and evaluation in enolate alkylations and aldol reactions
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Homochiral β-amino esters (prepared on multigram scale by lithium amide conjugate addition) are readily transformed into oxazinanones. N-Acyl derivatives of oxazinanones undergo stereoselective enolate alkylation reactions, with higher stereoselectivities observed for the enolate alkylation of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one than the corresponding Evans oxazolidin-2-one. A C(4)-iso-propyl stereodirecting group within the oxazinanone conveys higher stereoselectivity than the analogous C(4)-phenyl substituent. gem-Dimethyl substitution at C(6) within the oxazinanone framework facilitates exclusive exocyclic cleavage upon hydrolysis to furnish α-substituted carboxylic acid derivatives and the parent oxazinanone in good yield. Asymmetric aldol reactions of a range of aromatic and aliphatic aldehydes with the chlorotitanium enolate of (R)-N-propanoyl-4-iso- propyl-6,6-dimethyl-oxazinan-2-one proceed with excellent diastereoselectivity. Hydrolysis of the aldol products affords homochiral α-methyl-β- hydroxy-carboxylic acids. The Royal Society of Chemistry 2006.
- Davies, Stephen G.,Garner, A. Christopher,Roberts, Paul M.,Smith, Andrew D.,Sweet, Miles J.,Thomson, James E.
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p. 2753 - 2768
(2008/02/10)
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- Process for preparation of dicarboxylic acid monoesters
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A process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and a metal alkoxide to transesterification in the presence of an organic solvent, or a process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and an alcohol to transesterification in the presence of a metal alkoxide.
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- Chemo-enzymatic synthesis of chiral 2-substituted succinic acid derivatives
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Prochiral discrimination by the biocatalyst Alcalase, an enzyme preparation of subtilisin Carlsberg, was used to effect enantio- and regioselective monohydrolysis of a variety of (RS)-2-substituted succinate diesters to afford the corresponding half esters in modest to excellent enantiomeric excesses (>99%). Exploitation of malonate chemistry, as well as recycling of the unhydrolyzed isomer from the enantioselective hydrolysis, has resulted in a process which is both practical and economical.
- Bailey, Murray D.,Halmos, Ted,Adamson, Dan,Bordeleau, Josee,Grand-Maitre, Chantal
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p. 3285 - 3295
(2007/10/03)
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- A general method for the synthesis of enantiomerically pure β- substituted, β-amino acids through α-substituted succinic acid derivatives
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A general procedure for the synthesis of enantiopure β-substituted, β- amino acids is presented. Alkylation of the sodium enolates derived from chiral N-acyloxazolidinone imides 2 (R = Me, i-Pr, t-Bu, Ph, Bn) with tert- butyl bromoacetate afforded the 2-substituted succinate derivatives 3 in good yields (82-89%) and with high selectivity (≥ 93;7). Following hydrolysis, Curtius rearrangement of the resulting carboxylic acid provided the enantiopure benzyloxycarbonyl (Cbz)-protected β-amino esters 6 in good yields (74-79%).
- Evans, David A.,Wu, Leester D.,Wiener, John J. M.,Johnson, Jeffrey S.,Ripin, David H. B.,Tedrow, Jason S.
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p. 6411 - 6417
(2007/10/03)
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- Heterocyclic compouds
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A compound of the general formula wherein: n is 0 or 1; M1 is an amino group; Q is an aromatic heterocyclic group containing a basic nitrogen atom; M2 is an imino group; L is a template group; and A is an acidic group, or an ester or amide derivative thereof, or a sulphonamide group; and pharmaceutically acceptable salts and pro-drugs thereof, for use in the treatment of a disease in which platelet aggregation mediated by the binding of adhesion molecules to GPIIb-IIIa is involved. Novel compounds are also disclosed.
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- Dynamic Kinetic Resolution Utilizing 2-Oxoimidazolidine-4-carboxylate as a Chiral Auxiliary: Stereoselective Alkylation of α-Bromo Amides with Malonic Ester Enolates
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Stereoselective carbon-carbon bond formation by dynamic kinetic resolution using tert-butyl (4S)-1-methyl-2-oxoimidazolidine-4-carboxylate (1) as a chiral auxiliary was developed. Reaction of a diastereomeric mixture of tert-butyl (4S)-3-[(2RS)-2-bromoacyl]-1-methyl-2-oxoimidazolidine-4-carboxylates (2) with a malonic ester enolate in HMPA predominantly afforded tert-butyl (4S)-3-[(2R)-2-alkyl-3,3-bis(alkoxycarbonyl)propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylate [(S,R)-8] in good yields. The stereoselectivity of this reaction was in accordance with our working hypothesis based on the conformational analysis of 2 and elucidated the unique characteristics of 1 as a novel chiral auxiliary for dynamic kinetic resolution. The alkylated products (S,R)-8e,j,k were easily converted to chiral α-alkyl succinic acid derivatives and chiral β-amino acid derivatives, both of which have been known as key building blocks for the syntheses of a variety of biologically active compounds.
- Kubo, Akira,Kubota, Hitoshi,Takahashi, Masami,Nunami, Ken-Ichi
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p. 5830 - 5837
(2007/10/03)
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