- Scale-Up Synthesis of IID572: A New β-Lactamase Inhibitor
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The new potentially best-in-class β-lactamase inhibitor IID572 was discovered by a late-stage functionalization approach. An alternative synthesis was developed to satisfy the short-term material need for toxicological studies in animals. The new synthetic strategy was built on two key features, an intramolecular azomethine ylide [3 + 2] cycloaddition that allowed the efficient formation of molecular complexity from readily available starting materials and an enzymatic resolution that resulted in high optical purity of a key intermediate.
- Casarez, Anthony,Furegati, Markus,Koch, Guido,Nocito, Sandro,Reck, Folkert,Schuetz, Heiner,Simmons, Robert
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Read Online
- Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones
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Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections.
- Salas-Ambrosio, Pedro,Tronnet, Antoine,Since, Marc,Bourgeade-Delmas, Sandra,Stigliani, Jean-Luc,Vax, Amelie,Lecommandoux, Sébastien,Dupuy, Bruno,Verhaeghe, Pierre,Bonduelle, Colin
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supporting information
p. 3697 - 3702
(2021/04/07)
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- NOVEL SELECTIVE KAPPA OPIOID RECEPTOR ANTAGONISTS AND METHODS RELATED THERETO FOR TREATMENT OF ADDICTION AND NEUROPATHIC PAIN
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Disclosed is a composition and method for a therapeutic treatment that is able to combat certain conditions such as addiction, alcohol dependence, opioid abuse treatment, neurological disorders, neuropathic pain, and combinations thereof. The compounds act by acting as selective antagonist to the kappa (K) opioid receptor, which, when present leads to the inhibition of conditions, providing increased performance over known treatments. The disclosed compounds also shows the ability to cross the blood-brain-barrier in a highly efficient manner. The disclosed compounds are shown to be effective in the nanomolar range.
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Paragraph 00076
(2020/05/28)
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- Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist
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Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation
- Li, Xin,Wan, Hong,Dong, Ping,Wang, Bin,Zhang, Lei,Hu, Qiyue,Zhang, Ting,Feng, Jun,He, Feng,Bai, Chang,Zhang, Lianshan,Tao, Weikang
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supporting information
p. 2151 - 2155
(2020/12/17)
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- Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir
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Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an l-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative l-Phe-Sar dipeptide derivative 74 that gave four-fold improved AUC and eight-fold higher Ctrough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.
- Subbaiah, Murugaiah A.M.,Mandlekar, Sandhya,Desikan, Sridhar,Ramar, Thangeswaran,Subramani, Lakshumanan,Annadurai, Mathiazhagan,Desai, Salil D.,Sinha, Sarmistha,Jenkins, Susan M.,Krystal, Mark R.,Subramanian, Murali,Sridhar, Srikanth,Padmanabhan, Shweta,Bhutani, Priyadeep,Arla, Rambabu,Singh, Shashyendra,Sinha, Jaydeep,Thakur, Megha,Kadow, John F.,Meanwell, Nicholas A.
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supporting information
p. 3553 - 3574
(2019/04/17)
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- BETA-LACTAMASE INHIBITORS
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This invention pertains generally to compounds of Formula (A), as further described herein, which act as beta-lactamase inhibitors, and salts, crystalline forms and formulations thereof. In certain aspects, the invention pertains to methods of using such
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Paragraph 00203
(2018/04/17)
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- Structure-activity relationships of imidazole-derived 2-[ N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
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Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-a clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.
- Charton, Julie,Gauriot, Marion,Totobenazara, Jane,Hennuyer, Nathalie,Dumont, Julie,Bosc, Damien,Marechal, Xavier,Elbakali, Jamal,Herledan, Adrien,Wen, Xiaoan,Ronco, Cyril,Gras-Masse, Helene,Heninot, Antoine,Pottiez, Virginie,Landry, Valerie,Staels, Bart,Liang, Wenguang G.,Leroux, Florence,Tang, Wei-Jen,Deprez, Benoit,Deprez-Poulain, Rebecca
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p. 547 - 567
(2015/03/18)
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- ARYLPROPIONAMIDE, ARYLACRYLAMIDE, ARYLPROPYNAMIDE, OR ARYLMETHYLUREA ANALOGS AS FACTOR XIA INHIBITORS
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The present invention provides compounds of Formula (I) or (II): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L1, R3, R4, R8a, R11 and M are as defined herein. The compounds of Formula (I) or (II) are selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 63
(2010/02/17)
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- Weinreb amide based synthetic equivalents for convenient access to 4-aryl-1,2,3,4-tetrahydroisoquinolines
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New synthetic equivalents, N-methoxy-N-methyl-N′-phenylsulfonyl glycinamide and N-methoxy-N-methyl-N′-benzyl-N′-tert-butyloxy carbonyl glycinamide based on WA functionality were developed for the convenient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline framework. Two simple reactions, N-benzylation and addition of arylmagnesium halide on the WA functionality of the former afforded the key intermediate for convenient synthesis of N-phenylsulfonyl protected 4-aryl-1,2,3,4-tetrahydroisoquinoline, through reduction and acid promoted cyclization. With the latter, the addition of arylmagnesium halide on the WA functionality followed by the same protocol afforded the direct synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines in good yields. The acid promoted cyclization step enabled concomitant removal of N-Boc protection.
- Kommidi, Harikrishna,Balasubramaniam, Sivaraman,Aidhen, Indrapal Singh
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scheme or table
p. 3723 - 3729
(2010/07/05)
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- ARYLPROPIONAMIDE, ARYLACRYLAMIDE, ARYLPROPYNAMIDE, OR ARYLMETHYLUREA ANALOGS AS FACTOR XIA INHIBITORS
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The present invention provides compounds of Formula (I) or (II): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L1, R3, R4, R8a, R11 and M are as defined herein. The compounds of Formula (I) or (II) are selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 127
(2008/12/06)
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- IMIDAZOLIDINONE COMPOUNDS USEFUL AS BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE
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The present invention is directed to imidazolidinone compounds which are inhibitors of the beta- secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.
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Page/Page column 65
(2008/06/13)
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- Fluoro-olefins as peptidomimetic inhibitors of dipeptidyl peptidases
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The feasibility of the fluoro-olefin function as a peptidomimetic group in inhibitors for dipeptidyl peptidase IV and II (DPP IV and DPP II) is investigated by evaluation of N-substituted Gly-Ψ[CF=C]pyrrolidines, Gly-Ψ[CF=C]piperidines, and Gly-Ψ[CF=C](2-cyano)pyrrolidines. Of this later class, the (Z)- and (E)-fluoro-olefin analogues were prepared and chemical stability in comparison with the parent amide was checked. Most of these compounds exhibited a strong binding preference toward DPP II with IC 50 values in the low micromolar range, while only low DPP IV inhibitory potential is seen.
- Van Der Veken, Pieter,Senten, Kristel,Kertèsz, István,De Meester, Ingrid,Lambeir, Anne-Marie,Maes, Marie-Berthe,Scharpé, Simon,Haemers, Achiel,Augustyns, Koen
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p. 1768 - 1780
(2007/10/03)
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- A synthetic strategy for the preparation of cyclic peptide mimetics based on SET-promoted photocyclization processes
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A novel method for the synthesis of cyclic peptide analogues has been developed. The general approach relies on the use of SET-promoted photocyclization reactions of peptides that contain N-terminal phthalimides as light absorbing electron acceptor moieties and C-terminal α-amidosilane or α-amidocarboxylate centers. Prototypical substrates are prepared by coupling preformed peptides with the acid chloride of N-phthalimidoglycine. Irradiation of these substrates results in the generation of cyclic peptide analogues in modest to good yields. The chemical efficiencies of these processes are not significantly affected by (1) the lengths of the peptide chains separating the phthalimide and α-amidosilane or α-amidocarboxylate centers and (2) the nature of the penultimate cation radical α-heterolytic fragmentation process (i.e., desilylation vs decarboxylation). An evaluation of the effects of N-alkyl substitution on the amide residues in the peptide chain showed that N-alkyl substitution does not have a major impact on the efficiencies of the photocyclization reactions but that it profoundly increases the stability of the cyclic peptide.
- Yoon, Ung Chan,Jin, Ying Xue,Oh, Sun Wha,Park, Chan Hyo,Park, Jong Hoon,Campana, Charles F.,Cai, Xiaolu,Duesler, Eileen N.,Mariano, Patrick S.
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p. 10664 - 10671
(2007/10/03)
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- Analogues of arginine vasopressin (AVP) modified in the N-terminal part of the molecule with N-benzylglycine
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The synthesis and some pharmacological properties of five new analogues of arginine vasopressin (AVP) substituted with N-benzylglycine are described. All new peptides were tested for pressor and uterotonic activity. The results obtained imply that the structural change studied is in general incompatible with interaction of the analogues with V1A and OT receptors, however, in combination with suitable additional changes, may be of value in the design of new antagonists of these receptors.
- Jastrzebska,Derdowska,Kuncarowa,Slaninova,Lammek,Olejniczak,Zabrocki
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p. 823 - 830
(2007/10/03)
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- Antiherpes virus compounds and methods for their preparation and use
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This invention relates to methods for inhibiting herpes replication and for treating herpes infection in a mammal by inhibiting the herpes helicase-primase enzyme complex. This invention also relates to thiazolyphenyl derivatives that inhibit the herpes helicase-primase and to pharmaceutical compositions comprising the thiazolylphenyl derivatives, to methods of using and methods of producing the thiazolylphenyl derivatives
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- Anti-herpesvirus compounds and methods for identifying, making and using same
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This invention relates to methods for inhibiting herpes replication and for treating herpes infection in a mammal by inhibiting the herpes helicase-primase enzyme complex. This invention also relates to thiazolyphenyl derivatives that inhibit the herpes helicase-primase and to pharmaceutical compositions comprising the thiazolylphenyl derivatives, to methods of using and methods of producing the thiazolylphenyl derivatives.
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- N-Benzyl-N-(tert-butyloxycarbonyl)-glycine, an N-substituted glycine (peptoid) monomer
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The title compound, C14H19NO4, an amino acid mimic, was crystallized from ethyl acetate solution in a centrosymmetric space group. The distance between the side chain and the backbone was shorter than usually found in amino acids. The positional shift from α-carbon to nitrogen produced no significant steric hindrance between the side chain and the tert-butyl group.
- Doi, Mitsunobu,Kinoshita, Kazue,Asano, Akiko,Yoneda, Ryuji,Kurihara, Takushi,Ishida, Toshimasa
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p. 1164 - 1165
(2007/10/03)
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- Alkylation of chiral 2-(aminomethyl)oxazolines
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Chiral 2-(aminomethyl)oxazolines 3 and 7, in wich the heterocycle is derived from (R)-phenylglycinol, are synthesized and studied in alkylation reactions involving strong base and alkyl halides.The tertiary amine derivative 3 is alkylated efficiently at the α-carbon centre with no stereochemical induction, while the tertiary carbamate 7 is alkylated in moderate yield and reasonable diastereomeric excess.The stereochemical control observed in the latter case can be explained by the preferred formation of an E-enolate during the deprotonation step by prior complexation of the carbaamate carbonyl group to the base.
- Bail, Marc Le,Aitken, David J.,Vergne, Fabrice,Husson, Henri-Philippe
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p. 1681 - 1690
(2007/10/03)
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- Bradykinin receptor antagonists containing N-substituted amino acids: In vitro and in vivo B2 and B1 receptor antagonist activity
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We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B2) receptor for antagonist activity by incorporating N-alkyl-amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-A
- Goodfellow, Val S.,Marathe, Manoj V.,Kuhlman, Karen G.,Fitzpatrick, Timothy D.,Cuadrado, David,Hanson, Wendy,Zuzack, John S.,Ross, Sherman E.,Wieczorek, Maciej,Burkard, Michael,Whalley, Eric T.
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p. 1472 - 1484
(2007/10/03)
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- Polypeptide having an amino acid replaced with N-benzylglycine
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The present invention relates to one or more polypeptides having useful biological activity in a mammal, which comprise:a polypeptide related to bradykinin of four to ten amino acid residues wherein one or more specific amino acids in the polypeptide chai
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- An expedient enantioselective synthesis of N-t-Boc-protected phenylsarcosine
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Herein we describe a novel approach to the asymmetric synthesis of N-t-Boc-phenylsarcosine. The synthesis involves the enantioselective deprotonation at the benzylic position of N-t-Boc-N-methylbenzylamine 2 using the chiral complex s-BuLi/(-) sparteine 1
- Voyer, Normand
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p. 6627 - 6630
(2007/10/02)
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- Peptide Enolates. C-Alkylation of Glycine Residues in Linear Tri-, Tetra-, and Pentapeptides via Dilithium Azadienediolates
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The Boc-protected tripeptides Boc-Val-Gly-Leu-OH (1), Boc-Leu-Sar-Leu-OH (2), Boc-Leu-Gly-MeLeu-OH (3), and Boc-Val-BzlGly-Leu-OMe (64), tetrapeptide Boc-Leu-Gly-Pro-Leu-OH (9), and pentapeptides Boc-Val-Leu-Gly-Abu-Ile-OH (4), Boc-Val-Leu-Sar-MeAbu-Ile-O
- Bossler, Hans G.,Seebach, Dieter
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p. 1124 - 1165
(2007/10/02)
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- Preparation of N-Boc N-alkyl glycines for peptoid synthesis
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A series of N-tert-butoxycarbonylated N-allyl, N-propargyl, N-benzyl or branched N-alkyl glycines, useful building blocks for the synthesis of N-alkyl glycine oligomers, have been prepared by N-alkylation of N-Boc glycine or by a two-step method: reductive alkylation and tert-butoxycarbonylation.
- Mouna,Nguyen,Rage,Xie,Nee,Mazaleyrat,Wakselman
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p. 2429 - 2435
(2007/10/02)
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- Analogues of 2'(3')-O-L-phenylalanyladenosine as substrates and inhibitors of ribosomal peptidyltransferase
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The chemical syntheses of 2'(3')-O-(L-3-amino-3-phenylpropionyl)adenosine (2e), the corresponding D stereoisomer 2f, 2'(3')-O-(DL-phenylglycyl)adenosine (2g), 2'(3')-O-(N-benzylglycyl)adenosine (2h), and 9-(2-O-L-phenylalanyl-β-D-xylofuranosyl)adenine (3b) are described. Compounds 2e-h were obtained by acylation of 5'-O(4-methoxytrityl)adenosine with the appropriate N-benzyloxycarbonyl or N-tert-butoxycarbonyl amino acids with dicyclohexylcarbodiimide in pyridine. The corresponding reaction of N-(benzyloxycarbonyl)-D-phenylglycine led to an almost complete racemization of the aminoacyl residue (compounds 2c and 2g). Subsequent chromatographic separation and deprotection of intermediates 2a-d afforded the desired target derivatives 2e-h. Product 3b was obtained by a similar acylation of 9-(3,5-O-isopropylidene-β-D-xylofuranosyl)adenine with N-(benzyloxycarbonyl)-L-phenylalanine, followed by deblocking. The NMR spectra of 2' and 3' isomers of stereoisomers 2a and 2b are discussed. Compounds 2g and 3b are both substrates and inhibitors of Escherichia coli ribosomal peptidyltransferase, although the activity of 3b is low. Derivatives 2e,f,h do not accept AcPhe from N-AcPhe-tRNA in a peptidyltransferase-catalyzed reaction, but they inhibit the puromycin reaction in the same system. The order of inhibitory activity is 2e>2f>2h. The implications of these findings for the mechanism of peptidyltransferase and comparison of the latter with the action of chymotrypsin are discussed.
- Zemlicka,Bhuta,Bhuta
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p. 167 - 174
(2007/10/02)
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