- Discovery of Benzoazepinequinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors
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A novel benzoazepinequnoline (BAQ) series was discovered as RSV fusion inhibitors. BAQ series originated from compound 2, a hit from similarity-based virtual screening. In SAR exploration, benzoazepine allowed modifications in the head moiety. Benzylic sulfonyl on benzoazepine and 6-Me on quinoline were crucial for good anti-RSV activity. Although the basic amine in the head portion was crucial for anti-RSV activity, the attenuated basicity was required to reduce Vss. Introducing oxetane to the head portion led to discovery of compound 1, which demonstrated single-digit nM anti-RSV activity against different RSV strains, reasonable oral exposure in plasma, and 78-fold higher exposure in lung. Compound 1 also displayed 1 log viral reduction in a female BALB/c mice RSV model by b.i.d. oral dosing at 12.5 mg/kg. A single resistant mutant at L138F in fusion protein proved compound 1 to be a RSV fusion inhibitor.
- Zheng, Xiufang,Liang, Chungen,Wang, Lisha,Wang, Baoxia,Liu, Yongfu,Feng, Song,Wu, Jim Zhen,Gao, Lu,Feng, Lichun,Chen, Li,Guo, Tao,Shen, Hong C.,Yun, Hongying
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- Effect of ring size or an additional heteroatom on the potency and selectivity of bicyclic benzylamine-type inhibitors of phenylethanolamine N- methyltransferase
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In the search for potent and selective inhibitors of the enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), we examined the effect of ring size or an additional heteroatom in the conformationally- restricted benzylamine-type PNMT inhibitors. Based on semiempirical calculations (MNDO) and molecular modeling studies, PNMT-inhibitory activity of these compounds seemed to be dependent on (a) the torsion angle between the plane of the aromatic ring and the endo N atom lone pair (τ2 angle), with the optimal value of τ2 being about -75°, and (b) the amount of steric bulk about the 3-position of 1,2,3,4-tetrahydroisoquinoline (5, THIQ). 2,3,4,5-Tetrahydro-1H-2-benzazepine (6) was found to have the highest selectivity (PNMT K(i) = 3.34 μM, α2 K(i) = 11 μM, selectivity = 3.2) as compared to other homologues of THIQ (PNMT K(i) = 9.67 μM, α2 K(i) = 0.35 μM, selectivity = 0.036). The higher PNMT-inhibitory activity of 6 was attributed to favorable steric interactions of the puckered methylene groups in the putative bioactive conformation of 6 at the PNMT active site, whereas unfavorable interactions of these puckered methylene groups at the α2- adrenoceptor were thought to be the cause of reduced α2 affinity of 6. No further enhancement of the selectivity of the benzazepine ring system could be obtained via introduction of a second heteroatom (N, O, S) at the 5- position in this ring system.
- Grunewald, Gary L.,Dahanukar, Vilas H.,Ching, Piao,Criscione, Kevin R.
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- HISTONE ACETYLTRANSFERASE (HAT) INHIBITOR AND USE THEREOF
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The present invention relates to a histone acetyltransferase (HAT) inhibitor. Provided are a compound represented by general formula I, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method therefor, a pharmaceutical composition comprising the same, and use thereof in the treatment of various HAT-related diseases or conditions.
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Paragraph 0048; 0051
(2021/02/25)
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- COMPOUNDS FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS DISEASE
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The invention relates to the compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2 and X are as defined in the description and claims, which are useful for the treatment or prophylaxis of RSV infection.
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Paragraph 0104; 0105
(2013/04/13)
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- COMPOUNDS FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS DISEASE
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A compound of formula (I) as well as pharmaceutically acceptable salt thereof, wherein R1, R2 and X are as defined in description and in claims, can be used as a medicament.
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Page/Page column 15-16
(2013/04/25)
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- Benzene-fused heterocycle derivatives and drugs containing the same as the active ingredient
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A benzene-fused heteroring derivative of formula (I) 1, wherein all symbols are the same as described in the specification, and a non-toxic salt thereof. The compound of formula (I) has an inhibitory activity against cysteine protease and therefore it is
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- Base-promoted aminoethylation of thiols with 2-oxazolidinones: A simple synthesis of 2-aminoethyl sulfides
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A simple synthesis of 2-aminoethyl sulfides using a base-promoted reaction of 2-oxazolidinones with thiols is described. An application of this method to the synthesis of chiral 2-aminoethyl sulfides and sulfur-containing heterocyclic compounds is also presented.
- Ishibashi, Hiroyuki,Uegaki, Masayuki,Sakai, Manami,Takeda, Yoshifumi
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p. 2115 - 2120
(2007/10/03)
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