Tag: M.W=150-200

Rabal, Obdulia; Sanchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Perez-Gonzalez, Marta; Garcia-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Saez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen published the artcile< Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors>, Name: Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is sildenafil vardenafil orthoaminoanilide synthesis antiAlzheimer SAR PDE5 histone deacetylase; Alzheimer’s disease; PDE5 inhibition; chemical probes; class I HDAC selective inhibition; dual inhibitors; in vivo test.

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer’s disease (AD), we have designed, synthesized, and tested novel chem. probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these mols. exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chem. series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biol. responses. The lead identification process led to compound I, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chem. probe; thus, I has been assayed in a mouse model of AD (Tg2576).

ACS Chemical Neuroscience published new progress about Alzheimer disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Name: Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Miah, Afjal H.; Smith, Ian E. D.; Rackham, Mark; Mares, Alina; Thawani, Aditya R.; Nagilla, Rakesh; Haile, Pamela A.; Votta, Bartholomew J.; Gordon, Laurie J.; Watt, Gillian; Denyer, Jane; Fisher, Don T.; Dace, Phoebe; Giffen, Paul; Goncalves, Andrea; Churcher, Ian; Scott-Stevens, Paul; Harling, John D. published the artcile< Optimization of a Series of RIPK2 PROTACs>, Synthetic Route of 89793-12-4, the main research area is PROTAC RIPK2 IAP binder drug optimization.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogs with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 mo duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

Journal of Medicinal Chemistry published new progress about Blood. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Synthetic Route of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Hwang, Long-Chih; Wang, Eng-Chi; Lee, Kuan-Han; Tzeng, Cherng-Chyi published the artcile< Synthetic and antiviral studies on certain acyclo-nucleosides of 5-substituted 6-azauracils>, Name: 6-Bromo-1,2,4-triazine-3,5(2H,4H)-dione, the main research area is azauracil acyclic nucleoside antitumor antiviral; acyclic nucleoside preparation antitumor antiviral.

In view of the unique biol. properties and chemotherapeutic activities exhibited by DHPG and 6-azauridine, we initiated the present study to explore new acyclic nucleosides in which acyclic residues were attached to 6-azauracil and its derivatives by a glycosidic linkage in an attempt to search for more potent antiviral and/or antitumor agents. Coupling of persilylated intermediates of 5-substituted 6-azauracils with 1,3-dibenzyloxy-2-chloromethoxypropane, 1-benzyloxy-3-bromo-2-chloromethoxypropane, and 1-benzyloxy-2-chloromethoxybutane, resp., afforded three new series of protected acyclic nucleosides which were deprotected to give 5-substituted 6-azauracil acyclo-nucleosides, e.g. I (R = H, Br, R1 = OH, Me). None of the compounds exhibited significant antiviral activities against herpes simplex viruses types 1 and 2.

Chinese Pharmaceutical Journal (Taipei, Taiwan) published new progress about Antitumor agents. 4956-05-2 belongs to class pyrimidines, and the molecular formula is C3H2BrN3O2, Name: 6-Bromo-1,2,4-triazine-3,5(2H,4H)-dione.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Nabih, I.; Kamel, Mohsen M.; Saddik, M. published the artcile< Synthesis of a new schistosomicide>, Formula: C3H2BrN3O2, the main research area is nitrothiazolylaminotriazinedione preparation schistosomicide; triazinedione nitrothiazolylamino preparation schistosomicide.

The triazinedione I was prepared in 65% yield by converting 2-amino-5-nitrothiazole to its Na salt and reaction with 5-bromo-6-azauracil. At 35 mg/kg day for 5 days orally in mice I gave ∼80% kill of Schistosoma mansoni.

Pharmazie published new progress about Schistosoma mansoni. 4956-05-2 belongs to class pyrimidines, and the molecular formula is C3H2BrN3O2, Formula: C3H2BrN3O2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Zhang, Haoyang; Wu, Wenkui; Feng, Chao; Liu, Zhaogang; Bai, Enhe; Wang, Xueyuan; Lei, Meng; Cheng, Hao; Feng, Huayun; Shi, Jingmiao; Wang, Jia; Zhang, Zhao; Jin, Tao; Chen, Shanshan; Hu, Shihe; Zhu, Yongqiang published the artcile< Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants>, Application In Synthesis of 5018-38-2, the main research area is dihydropyrroloquinoline preparation anticancer EGFR modulator; 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives; EGFR modulator; L858R/T790M double mutants; Non-small cell lung cancer.

Based upon the modeling binding mode of marketed AZD9291 (I) with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound II showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound II exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 5018-38-2 belongs to class pyrimidines, and the molecular formula is C5H4Cl2N2O, Application In Synthesis of 5018-38-2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Eweg, Jan K.; Mueller, Franz; Bebelaar, Dick; Van Voorst, Joop D. W. published the artcile< Spectral properties of isoalloxazines in the vapor phase>, Reference of 2244-11-3, the main research area is alloxazine vapor fluorescence spectra; isoalloxazine vapor fluorescence spectra.

Spectral properties of two alloxazine and six isoalloxazine derivatives were determined at high temperatures in the vapor phase and compared with spectra observed in solution Vapor phase spectrometry gave primary photophys. properties of the isolated chromophore. Fluorescence lifetimes in the vapor phase were <0.5-18 ns. An intramol. complex existed between the isoalloxazine moiety and its aliphatic side chain carrying a polar hydroxyl group. Direct photodissociation of the mol. in its 1st electronically excited singlet state was not very probable. Photochemistry and Photobiology published new progress about Fluorescence. 2244-11-3 belongs to class pyrimidines, and the molecular formula is C4H4N2O5, Reference of 2244-11-3.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Jirku, V.; Vorlova, V.; Skoda, J. published the artcile< Inhibitory effect of 5-bromo-6-azauracil on growth and cell division of Saccharomyces cerevisiae>, Safety of 6-Bromo-1,2,4-triazine-3,5(2H,4H)-dione, the main research area is bromoazauracil Saccharomyces growth cell division.

The approx. min. concentration of 5-bromo-6-azauracil (I) [4956-05-2] causing significant inhibition of growth and cell division of S. cerevisiae was 8 mM. Higher concentrations had no greater inhibitory effect. Between the addition of I and the onset of its effect, there was always a delay of 120 min. The effect of I was reversed by thymine [65-71-4], cytosine [71-30-7], uracil [66-22-8], or 5-bromouracil [51-20-7]. 6-Azauracil had no effect. Evidently, I stimulates a rapid lytic process; the delay in the initiation of this process does not eliminate the possibility that cell lysis is directly or indirectly induced by a derivative or a breakdown product of I.

Experientia published new progress about Cell division. 4956-05-2 belongs to class pyrimidines, and the molecular formula is C3H2BrN3O2, Safety of 6-Bromo-1,2,4-triazine-3,5(2H,4H)-dione.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Nunes, Joao; McGonagle, Grant A.; Eden, Jessica; Kiritharan, Girieshanie; Touzet, Megane; Lewell, Xiao; Emery, John; Eidam, Hilary; Harling, John D.; Anderson, Niall A. published the artcile< Targeting IRAK4 for Degradation with PROTACs>, Synthetic Route of 89793-12-4, the main research area is IRAK4 proteolysis targeted chimera PROTAC degradation cytokine.

Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a key mediator of innate immunity. IRAK4 overactivation is linked with several autoimmune diseases. To date, many IRAK4 inhibitors have been developed to block the protein’s kinase activity with the most advanced reaching Phase II clin. trials. Nevertheless, several reports suggest kinase activity is not disease-relevant in certain cell types, so removing scaffolding signaling in addition to IRAK4 kinase activity may offer a better therapeutic outcome. Herein, we describe the design and synthesis of an IRAK4 Proteolysis Targeted Chimera (PROTAC). We show that IRAK4 degradation induced by compound 9 leads to the inhibition of multiple cytokines in PBMCs. However, in IL-1β stimulated human dermal fibroblasts, inhibition of IL-6 and TNF-α release was not observed despite IRAK4 degradation Nonetheless, the possibility of targeting both IRAK4 kinase and scaffolding function could potentially lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncol. diseases.

ACS Medicinal Chemistry Letters published new progress about Autoimmune disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Synthetic Route of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Kakkar, Rita; Sarma, Bhupendra K.; Katoch, Vandana published the artcile< Theoretical study of the mechanism of proton transfer in tautomeric systems: alloxan>, Synthetic Route of 2244-11-3, the main research area is alloxan proton transfer mechanism MNDO AM1 MO.

Semiempirical SCF-MO studies of tautomerism in alloxan preclude the possibility of direct proton transfer in the gas phase due to the strain in the four-centered transition state, in which the proton being transferred is forced to come close to the pos. charged carbon atom at the opposite corner of the four-membered ring. However, in aqueous solution, the activation barrier reduces appreciably, not only due to reduction in strain, but also due to charge separation in the transition state, which is stabilized due to ionic resonance. The N-H bond is almost broken, while the O-H bond is only partially formed in the transition state. The other stabilizing effect in aqueous solution is due to bulk solvent dielec. effects, which stabilize the transition state to a greater extent due to its higher dipole moment. Although the transition states for proton transfer to the neighboring oxygen atoms on either side have comparable energies, as the mechanisms of proton transfer leading to the formation of the 2-hydroxy and 4-hydroxy tautomers are similar, bulk solvent effects are larger in the latter due to the higher dipole moment of the transition state. The reason is the almost complete separation of the two entities, i.e. the alloxan anion and the hydronium ion in the latter case, indicating that in this case a dissociative mechanism of the kind encountered in acid-base equilibrium is operating.

Proceedings – Indian Academy of Sciences, Chemical Sciences published new progress about Activation energy (tautomerization). 2244-11-3 belongs to class pyrimidines, and the molecular formula is C4H4N2O5, Synthetic Route of 2244-11-3.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Takamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morishita, Ken-ichi; Matsuura, Nobuyasu; Makishima, Makoto; Ali, Hamed Ismail; Akaho, Eiichi; Tai, Akihiro; Sasaki, Kenji; Kakuta, Hiroki published the artcile< Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRα-preferential agonist possessing a sulfonamide moiety>, Formula: C7H7ClN2O2, the main research area is sulfonamide derivative preparation structure RXR agonist lipophilicity antitumor.

Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus the authors aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, compound (I) was found to prefer RXRα over RXRβ and RXRγ, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, the results suggest that the reduction of lipophilicity at the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. The finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.

ChemMedChem published new progress about Homo sapiens. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Formula: C7H7ClN2O2.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia