80021-60-9Relevant academic research and scientific papers
DIARYLUREAS AS CB1 ALLOSTERIC MODULATORS
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Paragraph 69; 72; 74, (2018/12/02)
The present invention provides novel diarylurea derivatives (compounds of formula (I)) and their uses. The compounds of the present invention are demonstrated to be allosteric modulators of the CB1 receptor, and therefore useful for the treatment of diseases and conditions mediated by CB1.
Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution
Nguyen, Thuy,German, Nadezhda,Decker, Ann M.,Langston, Tiffany L.,Gamage, Thomas F.,Farquhar, Charlotte E.,Li, Jun-Xu,Wiley, Jenny L.,Thomas, Brian F.,Zhang, Yanan
, p. 7410 - 7424 (2017/09/22)
Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (2). Similar to 2, these diarylureas dose-dependently inhibited CP55,940-induced intracellular calcium mobilization and [35S]GTP-γ-S binding while enhancing [3H]CP55,940 binding to the CB1 receptor. Structure-activity relationship studies revealed that the pyridinyl ring of 2 could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. 34 (RTICBM-74) had similar potencies as 2 in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, 34 was more effective than 2 in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction.
Meta-Selective CAr-H Nitration of Arenes through a Ru3(CO)12-Catalyzed Ortho-Metalation Strategy
Fan, Zhoulong,Ni, Jiabin,Zhang, Ao
supporting information, p. 8470 - 8475 (2016/07/26)
The first example of transition metal-catalyzed meta-selective CAr-H nitration of arenes is described. With the use of Ru3(CO)12 as the catalyst and Cu(NO3)2·3H2O as the nitro source, a wide spectrum of arenes bearing diversified N-heterocycles or oximido as the directing groups were nitrated with meta-selectivity exclusively. Mechanism studies have demonstrated the formation of a new 18e-octahedral ruthenium species as a key ortho-CAr-H metalated intermediate, which may be responsible for the subsequent meta-selective electrophilic aromatic substitution (SEAr). Moreover, this approach provides a fast-track strategy for atom/step economical synthesis of many useful pharmaceutical molecules.
Pyridine compounds and their pharmaceutical use
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, (2008/06/13)
A compound of formula (I) wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO), and are useful for prevention and/or treatment of NOS(nitric oxide synthasey)-mediated diseases such as adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-ependent diabetes mellitus, ulcerative colitis, cerebral infarction, rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, pain, ulcer, and the like in human being and animals.
Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists
Young,Mitchell,Brown,Ganellin,Griffiths,Jones,Rana,Saunders,Smith,Sore,Wilks
, p. 656 - 671 (2007/10/02)
A rational approach to the design of centrally acting agents is presented, based initially upon a comparison of the physicochemical properties of three typical histamine H2 receptor antagonists which do not readily cross the blood-brain barrier with those of the three brain-penetrating drugs clonidine (6), mepyramine (7), and imipramine (8). A good correlation was found between the logarithms of the equilibrium brain/blood concentration ratios in the rat and the partition parameter, Δ log P, defined as log P (1-octanol/water) - log P (cyclohexane/water), which suggests that brain penetration might be improved by reducing overall hydrogen-bonding ability. This model has been employed as a guide in the design of novel brain-penetrating H2 antagonists by the systematic structural modification of representatives of different structural types of H2 antagonists. Although marked increases in brain penetration amongst congeners of cimetidine (1), ranitidine (9), and tiotidine (10) were achieved, no compound was found with an acceptable combination of H2 antagonist activity (-log K(B) in the guinea pig atrium > 7.0) and brain penetration (steady-state brain/blood concentration ratio > 1.0). Conversely, structural modification of N-[[(piperidinylmethyl)phenoxy]propyl]acetamide (30) led to several potent, novel compounds which readily cross the blood-brain barrier. One of these, zolantidine (SK&F 95282, 41), whose -log K(B) is 7.46 and steady-state brain/blood ratio is 1.4, has been identified for use in studying histaminergic H2 receptor mechanisms in brain. Comparison of Δ log P values with the logarithms of the brain/blood ratios for 20 structurally diverse compounds for which data became available confirms a highly significant correlation and supports the general validity of this model.
