103301-78-6Relevant articles and documents
Design and synthesis of novel antihypertensive drugs
Moutevelis-Minakakis,Gianni,Stougiannou,Zoumpoulakis,Zoga,Vlahakos,Iliodromitis,Mavromoustakos
, p. 1737 - 1740 (2003)
AT1 antagonists constitute a new generation of drugs for the treatment of hypertension and are designed and synthesized to mimic the C-terminal segment of Angiotensin II (Ang II) and to block its binding action on AT1 receptor. For this reason, the conformational analysis of Ang II and its derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules were studied. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists and to design and synthesize new analogues with better pharmacological and financial profiles. An example of a novel synthetic non-peptide molecule is given which mimics the His6-Pro7-Phe8 part of Ang II and is based on the (S)-pyroglutamic acid.
Structure activity relationship studies of 17-cyclopropylmethyl-3,14β- dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido) morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function
Yuan, Yunyun,Elbegdorj, Orgil,Beletskaya, Irina O.,Selley, Dana E.,Zhang, Yan
, p. 5045 - 5048 (2013)
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α- (isoquinoline-3′-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1′- or 4′-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQ analogues retained low efficacy at the MOR compared to NAQ in the 35S- GTP[γS] binding assays while electron-withdrawing groups at 1′-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1′- or 4′-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation.
Diastereoselective alkylation of 1-benzyl-(5S)-substituted 2-pyrrolidinones
Brena-Valle, Leonardo J.,Sanchez, Rodolfo Carreon,Cruz-Almanza, Raymundo
, p. 1019 - 1026 (1996)
The (S)-glutamic acid derivatives, (5S)-methoxymethyl- and (5S)-benzyloxymethyl N-benzyl-2-pyrrolidinones, compounds 3a and 3b respectively, exhibit good to excellent diastereoselection upon alkylation with primary alkyl bromides or iodides.
Rhodium-Catalyzed Stereospecific C?H Amination for the Construction of Spiroaminal Cores: Reactivity Difference between Nitrenoid and Carbenoid Species against Amide Functionality
Kono, Masato,Harada, Shingo,Nemoto, Tetsuhiro
supporting information, p. 7428 - 7432 (2017/06/06)
Metal nitrenoids and metal carbenoids exhibit similar reactivity for insertion into a C?H bond and a C=C double bond. These reactions have attracted the attention of organic chemists due to their unusual bond-forming ability, but the reactivity difference between these chemical species has not been studied. In this paper, we examined the reactivity difference using the corresponding Rh nitrenoid and Rh carbenoid precursors. The Rh nitrenoid inserted into an intramolecular C(sp3)?H bond adjacent to an amide nitrogen, affording functionalized spiroaminals that are ubiquitous in natural products, while the Rh carbenoid inserted into an amide C?N bond. The totally different reactivity was rationalized by the relatively low energy barrier for the C?H insertion reaction of the Rh nitrenoid. Computational analysis suggests that the origin of the discrepancy is the electrophilicity of the coordinating atoms to the Rh complex.
Synthesis and evaluation of dual antiplatelet activity of bispidine derivatives of N-substituted pyroglutamic acids
Misra, Ankita,Anil Kumar,Jain, Manish,Bajaj, Kirti,Shandilya, Shyamali,Srivastava, Smriti,Shukla, Pankaj,Barthwal, Manoj K.,Dikshit, Madhu,Dikshit, Dinesh K.
, p. 1 - 12 (2016/01/29)
N-aralkylpyroglutamides of substituted bispidine were prepared and evaluated for their ability to inhibit collagen induced platelet aggregation, both in vivo and in vitro. Some compounds showed high anti-platelet efficacy (in vitro) of which six inhibited
3,7-DIAZABICYCLO[3.3.1 ]NONANE CARBOXAMIDES AS ANTITHROMBOTIC AGENTS
-
Page/Page column 14; 15, (2015/04/15)
The present invention relates to the 3,7-diazabicyclo[3.3.1]nonane carboxamides and process for preparation thereof. The present invention further relates to the compounds of general formula (1) possessing anti-thrombotic (anti-platelet) activities. The invention also relates to use of these moieties as inhibitors of collagen induced platelet adhesion and aggregation mediated through collagen receptors both in vitro and in vivo. Further, invention also relates these class of compounds exhibiting anti-platelet efficacy through dual mechanism inhibited both collagen as well as U46619 (thromboxane receptor agonist) induced platelet aggregation. General formula (1) Wherein, R' is; wherein R is selected from alkyl, acyl, tosyl, tert-butyloxycarbonyl, araalkyl or substituted araalkyl groups; R'' is selected preferably from halogen, cyano, lower alkyl, aryl, substituted aryl, and tosyl groups; R1 is selected from hydrogen and lower alkyl groups; R2 is selected from lower alkyl and aryl groups; R3 is selected from tert-butyloxycarbonyl and bezyloxycarbonyl groups; n = 0,1.
Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands
Yuan, Yunyun,Zaidi, Saheem A.,Stevens, David L.,Scoggins, Krista L.,Mosier, Philip D.,Kellogg, Glen E.,Dewey, William L.,Selley, Dana E.,Zhang, Yan
, p. 1701 - 1715 (2015/03/30)
A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′- and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6′-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.
Synthesis and identification of chiral aminomethylpiperidine carboxamides as inhibitor of collagen induced platelet activation
Anil Kumar,Misra, Ankita,Siddiqi, Tanveer Irshad,Srivastava, Stuti,Jain, Manish,Bhatta, Rabi Sankar,Barthwal, Manoj,Dikshit, Madhu,Dikshit, Dinesh K.
, p. 456 - 472 (2014/06/09)
A series of chiral lactam carboxamides of aminomethylpiperidine were synthesized and investigated for the collagen induced in vitro anti-platelet efficacy and collagen plus epinephrine induced in vivo pulmonary thromboembolism. The compound 31a (30 μM/kg) displayed a remarkable antithrombotic efficacy (60% protection) which was sustained for more than 24 h and points to its excellent bioavailability. The compounds 31a (IC50 = 6.6 μM) and 32a (IC50 = 37 μM), as well as their racemic mixture 28i (IC50 = 16 μM) significantly inhibited collagen-induced human platelet aggregation in vitro. Compound 34c displayed dual mechanism of action against both collagen (IC50 = 3.3 μM) and U46619 (IC50 = 2.7 μM) induced platelet aggregation. The pharmacokinetic study of 31a indicated very faster absorption, prolonged and constant systemic exposure and thereby exhibiting better therapeutic response.
An efficient and straight forward synthesis of (5S)-1-benzyl-5-(1H- imidazol-1-ylmethyl)-2-pyrrolidinone (MM1): A novel antihypertensive agent
Prasad, Jagdish,Pathak, Manoher Bhushan,Panday, Sharad Kumar
, p. 321 - 324 (2012/08/28)
(5S)-1-benzyl-5-(1H-imidazol-1-ylmethyl)-2-pyrrolidinone and its closely related analog was synthesized from (S)-pyroglutaminol and imidazole or substituted imidazole using Mitsunobu reaction as the key step. Springer Science+Business Media, LLC 2010.
Straightforward and facile approach toward the n-derivatization of pyroglutamates through mitsunobu reaction: Synthesis of N-alkyl/N-acyl pyroglutamates
Panday, Sharad Kumar,Prasad, Jagdish,Pathak, Manoher Bhushan
experimental part, p. 3654 - 3661 (2011/10/09)
Pyroglutamates have been acknowledged as useful chiral synthons for the synthesis of many bioactive natural products, ACE inhibitors, and conformationally constrained peptides. Though the reactivity differences between two differential carbonyl groups have been well exploited, there is still a dearth of publications on the N-alkylation/acylation of native pyroglutamate as such, due to the relatively low reactivity of NH of pyroglutamates. In the present communication, we report for the first time a simple and efficient methodology for the N-alkylation/acylation of pyroglutamate via Mitsunobu reaction. Copyright Taylor & Francis Group, LLC.
