14248-22-7Relevant academic research and scientific papers
Rational design of cannabinoid type-1 receptor allosteric modulators: Org27569 and PSNCBAM-1 hybrids
Nguyen, Thuy,Gamage, Thomas F.,Decker, Ann M.,Finlay, David B.,Langston, Tiffany L.,Barrus, Daniel,Glass, Michelle,Harris, Danni L.,Zhang, Yanan
, (2021/05/26)
Allosteric modulation offers an alternate approach to target the cannabinoid type-1 receptor (CB1) for therapeutic benefits. Examination of the two widely studied prototypic CB1 negative allosteric modulators (NAMs) Org27569 and PSNCBAM-1 revealed structural resemblance and similar structure–activity relationships (SARs). In silico docking and dynamics simulation studies using the crystal structure of CB1 co-bound with CP55,940 and Org27569 suggested that Org27569 and PSNCBAM-1 occupied the same binding pocket and several common interactions were present in both series with the CB1 receptor. A new scaffold was therefore designed by merging the key structural features from the two series and the hybrids retained these binding features in the in silico docking studies. In addition, one such hybrid displayed similar functions to Org27569 in dynamic simulations by preserving a key R2143.50-D3386.30 salt bridge and maintaining an antagonist-like Helix3-Helix6 interhelical distance. Based on these results, a series of hybrids were synthesized and assessed in calcium mobilization, [35S]GTPγS binding and cAMP assays. Several compounds displayed comparable potencies to Org27569 and PSNCBAM-1 in these assays. This work offers new insight of the SAR requirement at the allosteric site of the CB1 receptor and provides a new scaffold that can be optimized for the development of future CB1 allosteric modulators.
SUBSTITUTED, SATURATED AND UNSATURATED N-HETEROCYCLIC CARBOXAMIDES AND RELATED COMPOUNDS FOR THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
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Paragraph 00484, (2021/04/01)
The invention provides substituted, saturated and unsaturated N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
UREA DERIVATIVES AS CB1 ALLOSTERIC MODULATORS
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Page/Page column 78, (2021/01/23)
Heteroaryl and aliphatic analogs of diarylurea-based cannabinoid 1 receptor (CB1 R) allosteric modulators of formula (I) are described. Exemplary analogs can provide improved potencies and pharmacokinetic properties. Methods of using the analogs to treat
Sterically congested ester formation from α-substituted malononitrile and alcohol by an oxidative method using molecular oxygen
Hayashi, Yujiro,Li, Jing,Asano, Hirotaka,Sakamoto, Daisuke
supporting information, p. 675 - 677 (2018/11/23)
A metal-free oxidative esterification or thio-esterifica-tion of readily available substituted malononitrile and alcohol or thiol has been developed by simply mixing α-substituted malononitrile and alcohol or thiol in the presence of base under a molecular oxygen atmosphere. Sterically hindered ester or thioester can be prepared efficiently.
Decarboxylative Giese-Type Reaction of Carboxylic Acids Promoted by Visible Light: A Sustainable and Photoredox-Neutral Protocol
Ramirez, Nieves P.,Gonzalez-Gomez, Jose C.
supporting information, p. 2154 - 2163 (2017/04/24)
We describe herein a transition-metal-free method for the decarboxylative generation of radicals from carboxylic acids and their 1,4-addition to Michael acceptors. The Fukuzumi catalyst (9-mesitylene-10-methylacridinium perchlorate, [Acr-Mes]ClO4) enabled this transformation under visible-light irradiation at room temperature with CO2 as the only byproduct. The scope and limitations of this protocol were examined by using a range of Michael acceptors (15 examples) and carboxylic acids (18 examples). The use of 3-hydroxypivalic acid in this protocol allowed the straightforward formation of a diastereomerically pure δ-lactone. Moreover, when a homoallylic acid was used, a radical cascade reaction took place with the formation of three C–C bonds.
Nickel-catalysed direct alkylation of thiophenes via double C(sp3)-H/C(sp2)-H bond cleavage: The importance of KH2PO4
Wang, Xie,Xie, Peipei,Qiu, Renhua,Zhu, Longzhi,Liu, Ting,Li, You,Iwasaki, Takanori,Au, Chak-Tong,Xu, Xinhua,Xia, Yuanzhi,Yin, Shuang-Feng,Kambe, Nobuaki
supporting information, p. 8316 - 8319 (2017/07/26)
A Ni-catalyzed oxidative C-H/C-H cross-dehydrogenative coupling (CDC) reaction was developed for constructing various highly functionalized alkyl (aryl)-substituted thiophenes. This method employs thiophenes and aliphatic (aromatic) amides that contain an 8-aminoquinoline as a removable directing group in the presence of a silver oxidant. The approach enables the facile one-step synthesis of substituted thiophenes with high functional group compatibility via double C-H bond cleavage without affecting C-Br and C-I bonds. DFT calculations verify the importance of KH2PO4 as an additive for promoting C-H bond cleavage and support the involvement of a Ni(iii) species in the reaction.
Nickel-Catalyzed Addition-Type Alkenylation of Unactivated, Aliphatic C-H Bonds with Alkynes: A Concise Route to Polysubstituted γ-Butyrolactones
Li, Mingliang,Yang, Yudong,Zhou, Danni,Wan, Danyang,You, Jingsong
supporting information, p. 2546 - 2549 (2015/05/27)
(Chemical Equation Presented). Through the nickel-catalyzed chelation-assisted C-H bond activation strategy, the addition-type alkenylation of unreactive β-C(sp3)-H bonds of aliphatic amides with internal alkynes is developed for the first time to produce γ,δ-unsaturated carboxylic amide derivatives. The resulting alkenylated products can further be transformed into polysubstituted γ-butyrolactones with pyridinium chlorochromate (PCC).
Copper-catalyzed intramolecular C(sp3)-H and C(sp2)-H amidation by oxidative cyclization
Wang, Zhen,Ni, Jizhi,Kuninobu, Yoichiro,Kanai, Motomu
supporting information, p. 3496 - 3499 (2014/04/03)
The first copper-catalyzed intramolecular C(sp3)-H and C(sp 2)-H oxidative amidation has been developed. Using a Cu(OAc) 2 catalyst and an Ag2CO3 oxidant in dichloroethane solvent, C(sp3)-H
β-Arylation of carboxamides via iron-catalyzed C(sp3)-H bond activation
Shang, Rui,Ilies, Laurean,Matsumoto, Arimasa,Nakamura, Eiichi
supporting information, p. 6030 - 6032,3 (2013/05/22)
A 2,2-disubstituted propionamide bearing an 8-aminoquinolinyl group as the amide moiety can be arylated at the β-methyl position with an organozinc reagent in the presence of an organic oxidant, a catalytic amount of an iron salt, and a biphosphine ligand at 50 C. Various features of selectivity and reactivity suggest the formation of an organometallic intermediate via rate-determining C-H bond cleavage rather than a free-radical-type reaction pathway.
Pd(II)-catalyzed primary-C(sp3)-H acyloxylation at room temperature
Rit, Raja K.,Yadav, M. Ramu,Sahoo, Akhila K.
supporting information; experimental part, p. 3724 - 3727 (2012/08/28)
With the aid of a novel S-methyl-S-2-pyridyl-sulfoximine (MPyS) directing group (DG), the unactivated primary β-C(sp3)-H bond of MPyS-N-amides oxidizes at room temperature. The catalytic conditions are applicable to the diacetoxylation of primary β,β′-C(sp 3)-H bonds, and the carboxylic acid solvent is pivotal in the formation of the C-O bond. The MPyS-DG cleaves from the oxidation products and is recovered. This method provides convenient access to α,α′- disubstituted-β-hydroxycarboxylic acids.
