- MODIFIED DRUGS FOR USE IN LIPOSOMAL NANOPARTICLES
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Drag derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drag derivatized with a weak-base moiety that facilitates active loading of the drag through a LN transmembrane pH or ion gradient into the aqueous interior of the LN. The weak-base moiety can optionally comprise a lipophilic domain that facilitates active loading of the drag to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drag derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drags.
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Paragraph 0270; 0286-0287; 0292-0293
(2018/08/25)
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- Heterocycle derivatives and drugs
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The object of the invention is to provide an excellent compound as a drug. The invention relates to a heterocyclic compound shown by the following formula: A-B-D-E [1] wherein A is heteroaryl or its oxide; B is ethenylene; D is optionally substituted phenylene; and E is a group of the formula: ?wherein G is optionally substituted phenyl; and R is heteroaryl or heteroarylmethyl, or a group of the formula: ?wherein n is an integer of 1 to 5; R5 and R6 are same or different and are independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 taken together with the adjacent nitrogen atom may form 5- to 7-membered cyclic amino group for —NR5R6 or a salt thereof.
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- Symmetry-Based Inhibitors of HIV Protease. Structure-Activity Studies of Acylated 2,4-Diamino-1,5-diphenyl-3-hydroxypentane and 2,5-Diamino-1,6-diphenylhexane-3,4-diol
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The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described.Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends of the symmetric or pseudosymmetric inhibitors was probed.Aqueous solubility was enhanced >1000-fold while maintaining potent inhibition of purified HIV-1 protease and anti-HIV activity in vitro.Pharmacokinetic studies in rats indicated a substantial difference in the absorption properties of mono-ol-based and diol-based inhibitors.The oral bioavailability of inhibitor 19 in rats was 19percent; however, the Cmax obtained failed to exceed the anti-HIV EC50 in vitro.Substantial plasma levels of potent inhibitors of the diol class were not obtained after oral administration in rats; however, the optimal combination of aqueous solubility and in vitro antiviral activity of several inhibitors support their potential use in intravenous therapy.
- Kempf, Dale J.,Codacovi, Lynnmarie,Wang, Xiu Chun,Kohlbrenner, William E.,Wideburg, Norman E.,et al.
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p. 320 - 330
(2007/10/02)
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