- (S)-2-AMINO-6-((3-AMINOPROPYL)AMINO)HEXANOIC ACID (APL) FOR USE IN THE TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS (NASH), LIVER INFLAMMATION, HEPATOCELLULAR BALLOONING, LIVER FIBROSIS AND STEATOSIS
-
(S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (APL) for use in the treatment of non-alcoholic steatohepatitis (NASH), liver inflammation, hepatocellular ballooning, liver fibrosis and steatosis.
- -
-
Paragraph 00141
(2021/10/30)
-
- Protein synthesis with conformationally constrained cyclic dipeptides
-
We have synthesized several conformationally constrained dipeptide analogues as possible substrates for incorporation into proteins. These have included three cyclic dipeptides formed from Boc derivatives of 2,4-diaminobutyric acid, ornithine and lysine, having 5-, 6-, and 7-membered lactam rings, respectively. These dipeptides were used to activate a suppressor tRNA transcript, the latter of which had been prepared by in vitro transcription. Using modified E. coli ribosomes described previously, these activated suppressor tRNAs enabled the incorporation of the three cyclic dipeptides into dihydrofolate reductase (DHFR) at positions 18 and 49. The suppression yields increased with increasing lactam ring size and were found to proceed in suppression yields ranging from 3.4 to 8.9% at two different protein sites for the 5-, 6- and 7-membered lactam dipeptides. The greater facility of incorporation of the 7-membered lactam prompted us to prepare two 7-membered cyclic acylhydrazides (4 and 5) by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)-mediated cyclization of amino acids having selectively protected hydrazine functional groups in their side chains. In common with the lactam dipeptides, acylhydrazide dipeptides 4 and 5 could be used to activate the same suppressor tRNA transcript and to incorporate the cyclic dipeptides into DHFR. They were incorporated into the same two DHFR sites in suppression yields ranging from 8.3 to 11.2%.
- Bai, Xiaoguang,Dedkova, Larisa M.,Hecht, Sidney M.,Zhang, Chao
-
supporting information
(2020/10/02)
-
- COMPOSITIONS AND METHODS FOR TREATMENT OF INSULIN RESISTANCE
-
In certain embodiments, this disclosure relates to methods of treating or preventing type 2 diabetes, pre-diabetes and conditions characterized by an increase in the levels of AIC, glucose, insulin, homeostasis model of assessment of insulin resistance (HOMA-IR), oxidative stress in adipose tissue, and earbonvlation of GLUT4 comprising administering an effective amount of a compound of Formula I-III as described herein, to a subject in need thereof.
- -
-
Page/Page column 51; 52
(2019/10/01)
-
- COMPOSITIONS AND METHODS FOR TREATMENT OF INSULIN RESISTANCE
-
Compounds of Formula (I), and pharmaceutically effective salts thereof; wherein R1 - R14, m, n, o, p, q and r are as defined herein, are provided for treatment of for increasing insulin sensitivity, reducing insulin resistance, preventing insulin resistance and treating insulin resistance disorders.
- -
-
Paragraph 221
(2018/03/28)
-
- RIBOSOME-MEDIATED INCORPORATION OF PEPTIDES AND PEPTIDOMIMETICS
-
Modified ribosomes that were selected using a dipeptidyl-puromycin aminonucleoside are used to mediate site-specific incorporation of one or more peptides and peptidomimetics into protein in a cell free translation system. In addition, new fluorescent dipeptidomimetics have been synthesized and incorporated into proteins, as well as modified proteins containing one or more non-naturally occurring dipeptides.
- -
-
Paragraph 00214
(2016/08/17)
-
- Water compatible photoarylation of amino acids and peptides
-
A novel photoarylation of amino acids and peptides is described, which tolerates the presence of water. Irradiation of Boc-protected amino acids in the presence of N-protected 2-azidobenzimidazoles leads to selective arylation of carboxy termini or side chains. The new reaction also works for peptides. Irradiation of the nonapeptide H-SPSYVYHQF-OH also resulted in selective arylation of the tyrosine side chains, as indicated by ESI-MS/MS fragmentation. Chemo- and regioselectivity could add the title reaction to the repertoire of photoaffinity labeling methods.
- Sudakow, Alex,Papke, Uli,Lindel, Thomas
-
supporting information
p. 10223 - 10226
(2014/08/18)
-
- SUBSTITUTED ADIPIC ACID AMIDES AND USES THEREOF
-
The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A is a five to eight membered monocyclic or a nine to twelve membered bicyclic heterocyclic ring, as further defined herein; Y is S, CH2, or CH; Z is CH or N; R7 and R9 are hydrogen or (C1-C6)alkyl; R2 is (C1 C6)alkoxy, OH, CN, (C1-C6)alkyl, halogen, or CF3; r and s are 0, 1, or 2; and R1 and R3 are as further defined herein. These compounds are agonists, partial agonists and/or modulators of the NPY4 receptor and may be used for the treatment and prophylaxis of obesity, food intake, and other diseases and conditions modulated by the NPY4 receptor.
- -
-
Page/Page column 85
(2012/10/07)
-
- Efficient, solventless N-Boc protection of amines carried out at room temperature using sulfamic acid as recyclable catalyst
-
A simple, rapid, and efficient protocol for the chemoselective N-Boc protection of amines using sulfamic acid as catalyst is described. N-Boc protection of various structurally diverse aliphatic, aromatic, alicyclic, and heterocyclic amines (1°, 2°, 3°) was carried out with (Boc)2O using sulfamic acid as catalyst (5 mol %) at room temperature under solventless conditions. The advantages of this method are simplicity, shorter reaction times (1-15 min), a cost-effective catalyst, and excellent isolated yields (90-100%); it is also environmentally benign. Moreover, the combined use of ultrasound and sulfamic acid achieves a synergic effect that is especially marked in the N-Boc protection of deactivated (sterically hindered and electron-deficient) amines. The catalyst possesses distinct advantages: ease of handling, cleaner reactions, high activity, and excellent chemoselectivity.
- Upadhyaya, Dharita J.,Barge, Alessandro,Stefania, Rachele,Cravotto, Giancarlo
-
p. 8318 - 8322
(2008/04/13)
-
- Synthesis of a hexahydropyrimido[1,2-a]azepine-2-carboxamide derivative useful as an HIV integrase inhibitor
-
The hexahydropyrimido[1,2-a]azepine-2-carboxamide derivative 1 could be obtained by three synthetic strategies, which allowed access to multigram amounts of material of high purity and ee. Two strategies involved alternative approaches to the bicyclic pyrimidone core, with the most efficient one being a two-step sequence from commercially available starting materials exploiting a little precedented cyclisation reaction. The remaining steps to 1 included an efficient crystallisation of an intermediate as a single stereoisomer. An alternative strategy employing a chiral starting material led to products of low optical purity but allowed the assignment of the configuration of the stereogenic centre of 1.
- Ferrara, Marco,Crescenzi, Benedetta,Donghi, Monica,Muraglia, Ester,Nizi, Emanuela,Pesci, Silvia,Summa, Vincenzo,Gardelli, Cristina
-
p. 8379 - 8382
(2008/03/14)
-
- P38 INHIBITORS AND METHODS OF USE THEREOF
-
Compounds of formula (I): in which A, B, X, Ar1, R8 and R4 have any of the meanings given in the specification, are inhibitors of p38 useful in the treatment and prevention of various disorders mediated by p38.
- -
-
Page/Page column 62
(2008/06/13)
-
- Stereochemical diversity in asymmetric cyclization via memory of chirality
-
An enantiodivergent asymmetric cyclization of N-Boc-N-ω-bromoalkyl-α-amino acid derivatives has been developed. With potassium amide bases in DMF, cyclization proceeds with retention of configuration, while inversion of configuration was observed with lit
- Kawabata, Takeo,Matsuda, Seiji,Kawakami, Shimpei,Monguchi, Daiki,Moriyama, Katsuhiko
-
p. 15394 - 15395
(2007/10/03)
-
- Parallel liquid synthesis of N,N′-disubstituted 3-amino azepin-2-ones as potent and specific farnesyl transferase inhibitors
-
A rapid structure-activity study was performed by parallel liquid synthesis on N,N′-disubstitution of 3-amino azepin-2-one to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities. The activities of the selected compounds were validated in vivo, and compounds 41a and 44a presented significant antitumour activity.
- Le Diguarher, Thierry,Ortuno, Jean-Claude,Dorey, Gilbert,Shanks, David,Guilbaud, Nicolas,Pierre, Alain,Fauchere, Jean-Luc,Hickman, John A.,Tucker, Gordon C.,Casara, Patrick J.
-
p. 3193 - 3204
(2007/10/03)
-
- Novel, potent non-covalent thrombin inhibitors incorporating P3-lactam scaffolds
-
Evolution of P1-argininal inhibitor prototypes led to a series of non-covalent P3-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S1, S2, and S3 specificity pockets of thrombin. Rigid P1-arginine surrogates possessing a wide range of basicity (calcd pKa's～neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.
- Ho, Jonathan Z.,Gibson, Tony S.,Semple
-
p. 743 - 748
(2007/10/03)
-
- Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa
-
The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(s)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (K1 = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl2-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.
- Ewing, William R.,Becker, Michael R.,Manetta, Vincent E.,Davis, Roderick S.,Pauls, Henry W.,Mason, Helen,Choi-Sledeski, Yong Mi,Green, Daniel,Cha, Don,Spada, Alfred P.,Cheney, Daniel L.,Mason, Jonathan S.,Maignan, Sebastien,Guilloteau, Jean-Pierre,Brown, Karen,Colussi, Dennis,Bentley, Ross,Bostwick, Jeff,Kasiewski, Charles J.,Morgan, Suzanne R.,Leadley, Robert J.,Dunwiddie, Christopher T.,Perrone, Mark H.,Chu, Valeria
-
p. 3557 - 3571
(2007/10/03)
-
- Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics
-
We have previously shown that substitution of the D-Tic-Oic dipeptide by a (3S)-[amino]-5-(carbonylmethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (D-BT) moiety in the bradykinin B2 receptor antagonist HOE 140 resulted in a full potent and sel
- Amblard, Muriel,Daffix, Isabelle,Bergé, Gilbert,Calmès, Monique,Dodey, Pierre,Pruneau, Didier,Paquet, Jean-Luc,Luccarini, Jean-Michel,Bélichard, Pierre,Martinez, Jean
-
p. 4193 - 4201
(2007/10/03)
-
- Potent and selective thrombin inhibitors featuring hydrophobic, basic P3-P4-aminoalkyllactam moieties
-
Crystal structure and evolving SAR considerations of potent, selective benzylsulfonamide lactam thrombin inhibitors and related serine protease inhibitors have led to the design of novel thrombin inhibitors lag, featuring hydrophobic, basic, P4-alkylaminolactam scaffolds that serve as novel types of P3-P4 dipeptide mimics. The design, synthesis, and biological activity of these targets is presented.
- Semple, J. Edward,Rowley, David C.,Owens, Timothy D.,Minami, Nathaniel K.,Uong, Theresa H.,Brunck, Terence K.
-
p. 3525 - 3530
(2007/10/03)
-
- Alkoxide-catalyzed ring-opening of a novel homosaccharin derivative: Synthesis of potent, selective P3-lactam thrombin inhibitors containing P4- o-alkoxycarbonylbenzylsulfonamide residues
-
A series of lactam derivatives 1b-g featuring P4-o- alkoxycarbonylbenzylsulfonamide residues along with the potential P4- homosaccharin prodrug candidate 1h was prepared in order to probe the thrombin S3 specificity pocket. The synthesis and alkoxide-catalyzed ring opening of the novel homosaccharin intermediate 7 followed by subsequent elaboration delivered the targets 1b-h which were potent and selective thrombin inhibitors. The design, synthesis, and biological activity of these targets will be presented.
- Owens, Timothy D.,Semple, J. Edward
-
p. 3683 - 3688
(2007/10/03)
-
- Design and synthesis of conformationally-constrained MMP inhibitors
-
A novel series of conformationally constrained matrix metalloprotease inhibitors was identified. The potencies observed for these inhibitors were highly dependent upon the substitution pattern on the caprolactam ring as well as the succinate moiety.
- Natchus, Michael G.,Cheng, Menyan,Wahl, Christopher T.,Pikul, Stanislaw,Almstead, Neil G.,Bradley, Rimma S.,Taiwo, Yetunde O.,Mieling, Glen E.,Michelle Dunaway,Snider, Catherine E.,McIver, John M.,Barnett, Bobby L.,McPhail, Sara J.,Anastasio, Melanie B.,De, Biswanath
-
p. 2077 - 2080
(2007/10/03)
-
- SUBSTITUTED AZEPINONE DUAL INHIBITORS OF ANGIOTENSIN CONVERTING ENZYME AND NEUTRAL EXDOPEPTIDASE
-
Compounds of the formula STR1 are disclosed as possessing inhibitory activity against angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) and thus being useful as cardiovascular agents. Processes for preparing these compounds are also disclosed.
- -
-
-
- Synthesis and dopamine receptor modulating activity of lactam conformationally constrained analogues of Pro-Leu-Gly-NH2
-
A series of analogues of the potent analogue of Pro-Leu-Gly-NH2 (PLG), 2- oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide (2) were synthesized in which the (R)-γ-lactam residue of 2 was replaced with a (R)- β-lactam, (R)-aminosuccinimide, (R)-cycloseryl, (R)-δ-lactam, (R)-ε- lactam, or (S)-ε-lactam residue to give analogues 3-8, respectively. These substitutions were made so as to vary the ψ2 torsion angle. The analogues were tested for their ability to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor. Analogues 3-6 and 8 exhibited dose- response curves that were bell-shaped in nature with the maximum effect occurring at a concentration of 1 μM. Analogue 7 was inactive. Analogues 3 and 4 were found to be as effective as PLG, while analogues 5, 6, and 8 appeared to be more effective than PLG in terms of enhancing the binding of ADTN to dopamine receptors. The activity of analogues 3-6 and 8 with their ψ2 angles in the vicinity of that observed in a type II β-turn is consistent with the hypothesis that this type of turn is the bioactive conformation of PLG.
- Sreenivasan,Mishra,Johnson
-
p. 256 - 263
(2007/10/02)
-
- CERTAIN 3-PHOSPHINYL-AMINO-2-OXO-1H-AZEPINE-1-ACETIC ACID DERIVATIVES HAVING ANTI-HYPERTENSIVE ACTIVITY
-
Phosphonamide substituted lactams of the formula STR1 are disclosed. These compounds are useful as hypotensive agents.
- -
-
-
- LACTAM CONTAINING COMPOUNDS, THEIR PHARMACEUTICAL COMPOSITIONS AND METHOD OF USE
-
Compounds of the formula STR1 are disclosed wherein R is STR2 The compounds possess hypotensive activity.
- -
-
-
- STUDIES ON LACTAMS IX. A CONVENIENT SYNTHESIS OF LACTAM RINGS
-
The auto-cyclization reaction has been employed for the synthesis of lactam rings by means of reduction from ω-carbobenzoxyamino acid active esters in high dilution method.
- Ogura, Haruo,Takeda, Kazuyoshi
-
p. 467 - 468
(2007/10/02)
-
