- Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis
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The inhibition of corticosteroid biosynthesis could be considered as an emerging strategy to reduce their abnormally high levels, and in this framework CYP11B1 and CYP11B2 represent the most promising targets. In continuing our studies on flavonoid-like scaffolds as privileged structures in medicinal chemistry, in this paper we describe a small library of pyridyl- and imidazolylmethylchromones as potential inhibitors of these enzymes. Testing results proved that position 3 of the chromone scaffold is the most favorable for the introduction of the heme-coordinating heterocycles and, among them, the 4-imidazolyl moiety is the most convenient for the interaction with the heme iron of the selected cytochromes. A low nanomolar inhibitor of CYP11B1 (5c) was obtained, endowed with reasonable selectivity toward CYP11B2 and able to better discriminate with respect to CYP17 and CYP19.
- Gobbi, Silvia,Hu, Qingzhong,Zimmer, Christina,Engel, Matthias,Belluti, Federica,Rampa, Angela,Hartmann, Rolf W.,Bisi, Alessandra
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- Design, synthesis and biological evaluation of pyridyl substituted benzoxazepinones as potent and selective inhibitors of aldosterone synthase
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Exorbitant aldosterone is closely associated with various severe diseases, including congestive heart failure and chronic kidney disease. As aldosterone synthase is the pivotal enzyme in aldosterone biosynthesis, its inhibition constitutes a promising tre
- Zhu, Haichao,Liu, Meihua,Li, Haiyan,Guan, Ting,Zhang, Qi,Chen, Yang,Liu, Yingxiang,Hartmann, Rolf R.,Yin, Lina,Hu, Qingzhong
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- Steroid synthase inhibitors and therapeutic application thereof
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The invention discloses a steroid synthase inhibitor and treatment application thereof, and belongs to the field of medicines. The compound capable of being used as the medicine has the effect of inhibiting steroid synthase, is high in inhibition rate and
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- Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols: A versatile access to restricted iso combretastatin A-4 analogues as antitumor agents
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Potent anticancer 4-arylchromene agents 6, as restricted isoCA-4 analogues, were prepared with excellent yields by a rapid and versatile synthetic pathway. First, in the presence of PTSA in EtOH, a variety of arylalkynols 9 were transformed into substitut
- Renko, Dolor,Provot, Olivier,Rasolofonjatovo, Evelia,Bignon, Jér?me,Rodrigo, Jordi,Dubois, Jo?lle,Brion, Jean-Daniel,Hamze, Abdallah,Alami, Mouad
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p. 834 - 844
(2015/03/13)
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- Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application
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The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R3) at the para-position of the P1′ benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R1) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC50s on wild-type HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS.
- Kesteleyn, Bart,Amssoms, Katie,Schepens, Wim,Hache, Geerwin,Verschueren, Wim,Van De Vreken, Wim,Rombauts, Klara,Meurs, Greet,Sterkens, Patrick,Stoops, Bart,Baert, Lieven,Austin, Nigel,Wegner, J?rg,Masungi, Chantal,Dierynck, Inge,Lundgren, Stina,J?nsson, Daniel,Parkes, Kevin,Kalayanov, Genadiy,Wallberg, Hans,Rosenquist, ?sa,Samuelsson, Bertil,Van Emelen, Kristof,Thuring, Jan Willem
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p. 310 - 317
(2013/02/25)
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- SPIROAMINODIHYDROTHIAZINE DERIVATIVES
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A compound represented by the general formula (I): or a pharmaceutically acceptable salt thereof, has an Aβ production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Aβ and typified by Alzheimer- type dementia.
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Page/Page column 61
(2010/04/03)
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- PHARMACEUTICALLY ACTIVE 6-N-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES
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The invention provides compounds of the formula (0), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.
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- CHROMAN DERIVATIVES AND THEIR USE AS 5-HT RECEPTOR LIGANDS
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Compounds of the formula (I) or pharmaceutically acceptable salts thereof, wherein m, p, q, Ar, R1, R2, R3 and R4 are as defined herein. Also provided are methods for preparing, compositions comprising, and methods for using compounds of formula (I).
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Page/Page column 30
(2008/06/13)
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- CHROMAN DERIVATIVES AND USES THEREOF IN THE TREATMENT OF CNS DISORDERS
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Compounds of the formula (I): or pharmaceutically acceptable salts thereof, wherein m, p, q, Ar, R1, R2, R3 and R4 are as defined herein. Also provided are methods for preparing, compositions comprising, and met
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Page/Page column 24-25
(2008/06/13)
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- Quinoxaline compounds
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Certain amidophenyl-sulfonylamino-quinoxaline compounds are CCK2 modulators useful in the treatment of CCK2 mediated diseases.
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(2008/06/13)
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- BICYCLIC SUBSTITUTED INDOLE-DERIVATIVE STEROID HORMONE NUCLEAR RECEPTOR MODULATORS
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The present invention provides a compound of the formula: Formula (I); or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising an effective amount of a compound of Formula I in combination with a suitable carrier, diluent, or excipient, and methods for treating physiological disorders, particularly congestive heart disease, hypertension, and atherosclerosis, comprising administering to a patient in thereof an effective amount of a compound of Formula I. X-16125
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(2010/02/14)
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- Spirohydantoin compounds and uses thereof
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Spirohydantoin compounds and their pharmaceutically acceptable salts are disclosed. The synthesis of these compounds and their use as alpha 1a adrenergic receptor antagonists is also described. One application of these compounds is in the treatment of ben
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- 3-(benzofuran-7-yl)-6-haloalkyluracils
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Herbicidal 3-(benzofuran-7-yl)-6-haloalkyluracils of the formula STR1 in which M is fluoroalkyl (C1-6); D is hydrogen, alkyl (C1-6), or alkoxy(C1-6)-carbonyl; E is hydrogen or alkyl (C1-6), or D and E taken together are --CH2 CH2 --; R is hydrogen, amino, alkyl (C1-6), 2-alkenyl (C3-6), 2-alkynyl (C3-6), alkoxy(C1-6)methyl, benzyl, amino, fluoroalkyl (C1-6), alkoxy (C1-6)-carbonylmethyl; or cyanoalkyl (C1-6) having preferably one cyano group; X is hydrogen, fluorine, chlorine, bromine, cyano, alkyl(C1-6), haloalkyl(C1-6), haloalkoxy(C1-6), or alkoxy(C1-6); Y is hydrogen, alkyl (C1-6), fluorine, chlorine, or bromine; and Z is CH2, C=O, C=S, --CH(OH)--, --CH2 CH2 --, --CH=CH--, --(C=O)CH2 --; or C=N--O--R' wherein R' is alkyl(C1-6).
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