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1.
Eur J Med Chem ; 250: 115143, 2023 Mar 15.
Article in English | MEDLINE | ID: mdl-36841086

ABSTRACT

Recent discoveries have demonstrated that the physiological function of bile acids extends to the regulation of diverse signaling processes through interactions with nuclear and G protein-coupled receptors, most notably the Farnesoid-X nuclear receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Targeting such signaling pathways pharmacologically, i.e. with bile acid-derived therapeutics, presents great potential for the treatment of various metabolic, inflammatory immune, liver, and neurodegenerative diseases. Here we report the discovery of two potent and selective TGR5 agonists (NZP196 and 917). These compounds are the taurine conjugates of 6α-ethyl-substituted 12ß-methyl-18-nor-bile acids with the side chain being located on the α-face of the steroid scaffold. The compounds emerged from a screening effort of a diverse library of 12ß-methyl-18-nor-bile acids that were synthesized from 12ß-methyl-18-nor-chenodeoxycholic acid and its C17-epimer. Upon testing for FXR activity, both compounds were found to be inactive, thus revealing selectivity for TGR5.


Subject(s)
Bile Acids and Salts , Receptors, G-Protein-Coupled , Bile Acids and Salts/pharmacology , Receptors, G-Protein-Coupled/agonists , Signal Transduction , Liver/metabolism , Chenodeoxycholic Acid
2.
J Med Chem ; 65(7): 5462-5494, 2022 04 14.
Article in English | MEDLINE | ID: mdl-35324190

ABSTRACT

Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of S-adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics. Inhibitors causing both full and partial inhibition of purified DNMT1 were characterized. The inhibitors show modest selectivity for DNMT1 versus DNMT3b. Active-site docking predicts inhibitor interactions with S-adenosyl-l-methionine and deoxycytidine regions of the catalytic site, validated by direct binding analysis. Inhibitor action with purified DNMT1 is not reflected in cultured cells. A partial inhibitor activated cellular DNA methylation, and a full inhibitor had no effect on cellular DNA methylation. These compounds provide chemical access to a new family of noncovalent DNMT chemical scaffolds for use in DNA methyltransferases.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases , DNA Methylation , Cell Line , DNA/metabolism , DNA (Cytosine-5-)-Methyltransferase 1/metabolism , DNA Modification Methylases/metabolism , Deoxycytidine/metabolism , Humans
3.
Arch Pharm (Weinheim) ; 355(5): e2100497, 2022 May.
Article in English | MEDLINE | ID: mdl-35174898

ABSTRACT

The quest for isoform-selective and specific ATP-competitive protein kinase inhibitors is of great interest, as inhibitors with these qualities will come with reduced toxicity and improved efficacy. However, creating such inhibitors is very challenging due to the high molecular similarity of kinases ATP active sites. To achieve selectivity for our casein kinase (CK) 1 inhibitor series, we elected to endow our previous CK1δ-hit, 3-(4-fluorophenyl)-5-isopropyl-4-(pyridin-4-yl)isoxazole (1), with chiral iminosugar scaffolds. These scaffolds were attached to C5 of the isoxazole ring, a position deemed favorable to facilitate binding interactions with the ribose pocket/solvent-open area of the ATP binding pocket of CK1δ. Here, we describe the synthesis of analogs of 1 ((-)-/(+)-34, (-)-/(+)-48), which were prepared in 13 steps from enantiomerically pure ethyl (3R,4S)- and ethyl (3S,4R)-1-benzyl-4-[(tert-butyldimethylsilyl)oxy]-5-oxopyrrolidine-3-carboxylate ((-)-11 and (+)-11), respectively. The synthesis involved the coupling of Weinreb amide-activated chiral pyrrolidine scaffolds with 4- and 2-fluoro-4-picoline and reaction of the resulting 4-picolyl ketone intermediates ((-)-/(+)-40 and (-)-/(+)-44) with 4-fluoro-N-hydroxybenzenecarboximidoyl chloride to form the desired isoxazole ring. The activity of the compounds against human CK1δ, -ε, and -α was assessed in recently optimized in vitro assays. Compound (-)-34 was the most active compound with IC50 values (CK1δ/ε) of 1/8 µM and displayed enhanced selectivity toward CK1δ.


Subject(s)
Casein Kinase Idelta , Adenosine Triphosphate/metabolism , Casein Kinase Idelta/chemistry , Casein Kinase Idelta/metabolism , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Protein Kinase Inhibitors , Structure-Activity Relationship
4.
ACS Omega ; 6(38): 25019-25039, 2021 Sep 28.
Article in English | MEDLINE | ID: mdl-34604682

ABSTRACT

Decoupling the roles of the farnesoid X nuclear receptor and Takeda G-protein-coupled bile acid receptor 5 is essential for the development of novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. Herein, we describe the synthesis of 12ß-methyl-18-nor-bile acids which may serve as probes in the search for new bile acid analogues with clinical applicability. A Nametkin-type rearrangement was applied to protected cholic acid derivatives, giving rise to tetra-substituted Δ13,14- and Δ13,17-unsaturated 12ß-methyl-18-nor-bile acid intermediates (24a and 25a). Subsequent catalytic hydrogenation and deprotection yielded 12ß-methyl-18-nor-chenodeoxycholic acid (27a) and its 17-epi-epimer (28a) as the two major reaction products. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale. In addition, the first cis-C-D ring-junctured bile acid and a new 14(13 → 12)-abeo-bile acid are described. Furthermore, deuteration experiments were performed to provide mechanistic insights into the formation of the formal anti-hydrogenation product 12ß-methyl-18-nor-chenodeoxycholic acid (27a).

5.
Bioorg Med Chem ; 20(17): 5181-7, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22854195

ABSTRACT

Several acyclic hydroxy-methylthio-amines with 3-5 carbon atoms were prepared and coupled via a methylene link to 9-deazaadenine. The products were tested for inhibition against human MTAP and Escherichia coli and Neisseria meningitidis MTANs and gave K(i) values as low as 0.23 nM. These results were compared to those obtained with 1st and 2nd generation inhibitors (1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio-D-ribitol (MT-Immucillin-A, 3) and (3R,4S)-1-[9-deazaadenin-9-yl)methyl]3-hydroxy-4-methylthiomethylpyrrolidine (MT-DADMe-Immucillin-A, 4). The best inhibitors were found to exhibit binding affinities of approximately 2- to 4-fold those of 3 but were significantly weaker than 4. Cleavage of the 2,3 carbon-carbon bond in MT-Immucillin-A (3) gave an acyclic product (79) with a 21,500 fold loss of activity against E. coli MTAN. In another case, N-methylation of a side chain secondary amine resulted in a 250-fold loss of activity against the same enzyme [(±)-65 vs (±)-68]. The inhibition results were also contrasted with those acyclic derivatives previously prepared as inhibitors for a related enzyme, purine nucleoside phosphorylase (PNP), where some inhibitors in the latter case were found to be more potent than their cyclic counterparts.


Subject(s)
Adenosine/analogs & derivatives , Biomimetic Materials/pharmacology , Enzyme Inhibitors/pharmacology , N-Glycosyl Hydrolases/antagonists & inhibitors , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Pyrrolidines/pharmacology , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Humans , Ions/chemical synthesis , Ions/chemistry , Ions/pharmacology , Molecular Conformation , N-Glycosyl Hydrolases/metabolism , Neisseria meningitidis/enzymology , Purine-Nucleoside Phosphorylase/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Structure-Activity Relationship
6.
Acta Crystallogr C ; 66(Pt 8): o418-20, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20679720

ABSTRACT

The absolute configuration of the title cis-(1R,3R,4S)-pyrrolidine-borane complex, C(18)H(34)BNO(2)Si, was confirmed. Together with the related trans isomers (3S,4S) and (3R,4R), it was obtained unexpectedly from the BH(3) x SMe(2) reduction of the corresponding chiral (3R,4R)-lactam precursor. The phenyl ring is disordered over two conformations in the ratio 0.65:0.35. The crystallographic packing is dominated by the rarely found donor-acceptor hydroxy-borane O-H...H-B hydrogen bonds.


Subject(s)
Boranes/chemistry , Lactams/chemistry , Pyrrolidines/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship
7.
J Med Chem ; 52(4): 1126-43, 2009 Feb 26.
Article in English | MEDLINE | ID: mdl-19170524

ABSTRACT

ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe-ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K(d) = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.


Subject(s)
Adenine/analogs & derivatives , Drug Design , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Adenine/chemical synthesis , Adenine/chemistry , Adenine/pharmacology , Adenosine/analogs & derivatives , Catalytic Domain , Humans , Molecular Conformation , Pliability , Protein Binding , Pyrrolidines/chemical synthesis , Structure-Activity Relationship
8.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 5): o943, 2009 Apr 02.
Article in English | MEDLINE | ID: mdl-21583987

ABSTRACT

Mol-ecules of the title compound [systematic name: (2R,5S,7S)-2-phenyl-7-phenyl-sulfanyl-1-aza-3-oxa-bicyclo-[3.3.0]octan-8-one], C(18)H(17)NO(2)S, form high quality crystals even though they are only packed using C-H⋯O(carbon-yl) and weak C-H⋯S inter-actions. The dihedral angle between the aromatic rings is 85.53 (5)°. The fused rings adopt envelope and twist conformations.

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