ABSTRACT
The effective permeability (Peff) in the human jejunum (in vivo) of 22 structurally diverse compounds was correlated with both experimentally determined lipophilicity values and calculated molecular descriptors. The permeability data were previously obtained by using a regional in vivo perfusion system in the proximal jejunum in humans as part of constructing a biopharmaceutical classification system for oral immediate-release products. pKa, log P, and, where relevant, log Pion values were determined using the pH-metric technique. On the basis of these experiments, log D values were calculated at pH 5.5, 6.5, and 7.4. Multivariate data analysis was used to derive models that correlate passive intestinal permeability to physicochemical descriptors. The best model obtained, based on 13 passively transcellularly absorbed compounds, used the variables HBD (number of hydrogen bond donors), PSA (polar surface area), and either log D5.5 or log D6.5 (octanol/water distribution coefficient at pH 5.5 and 6.5, respectively). Statistically good models for prediciting human in vivo Peff values were also obtained by using only HBD and PSA or HBD, PSA, and CLOGP. These models can be used to predict passive intestinal membrane diffusion in humans for compounds that fit within the defined property space. We used one of the models obtained above to predict the log Peff values for an external validation set consisting of 34 compounds. A good correlation with the absorption data of these compounds was found.
Subject(s)
Intestinal Absorption , Jejunum/metabolism , Models, Biological , Pharmaceutical Preparations/metabolism , Humans , Multivariate Analysis , Permeability , Pharmaceutical Preparations/chemistry , Structure-Activity RelationshipABSTRACT
Ten C2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (1a and 2-5). Thirdly, compounds with hydrogen bond-accepting or-donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/enzymology , Mannitol/analogs & derivatives , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Azepines , Computer Simulation , HIV Protease/metabolism , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/metabolism , HIV-1/drug effects , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Mannitol/metabolism , Mannitol/pharmacology , Molecular Structure , Protein Binding , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/metabolism , Sulfonamides/pharmacology , Urea/analogs & derivatives , Urea/metabolism , Urea/pharmacologyABSTRACT
Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1' positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 A resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1' and P2' side chains were transposed.
Subject(s)
Azepines/chemistry , HIV Protease Inhibitors/chemistry , HIV Protease/chemistry , HIV-1/enzymology , Sulfonamides/chemistry , Azepines/metabolism , Azepines/pharmacology , Binding Sites , Crystallization , Crystallography, X-Ray , HIV Protease/metabolism , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacology , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Binding , Sulfonamides/metabolism , Sulfonamides/pharmacologyABSTRACT
The metabolic fates of 2-chloro-, 2-bromo-, 4-bromo- and 2-iodo-17 alpha-ethynyloestradiol (EE2) in rats were determined. 6,7-3H-labelled analogues (0.1-2.0 mumol/kg) were administered i.v. to anaesthetized animals. The metabolites of all four compounds were rapidly and extensively excreted in bile (79-93% of the dose over 6 h). Unlike EE2 and 2-fluoro-EE2 (2-FEE2), neither 2-chloro(Cl)-(2.0 mumol/kg),2-bromo(Br)-(0.1 mumol/kg), nor 2-iodo(I)-EE2-(0.1 mumol/kg) underwent C-2 hydroxylation in female rats; 2-BrEE2 was similarly refractory in male rats; females, was subject to approx. 2-fold greater C-2 hydroxylation than 2-FEE2 but this equalled only approx. 60% of that undergone by EE2. All three of the C-2 halogenated derivatives were substantially excreted unchanged except for conjugation. 2-ClEE2 alone was C-4 hydroxylated to an appreciable extent. The oxidative metabolism of 2- and 4-BrEE2 in rats was sexually differentiated: 2-BrEE2 yielded an alkyl hydroxylated metabolite and a two-component dihydroxylated fraction in the ratio 1:0.09 and 1:0.76 in males and females, respectively; 4-BrEE2 underwent C-2 and alicyclic (C-15) hydroxylation in the ratio 1:4.8 and 1:0.07 in males and females, respectively. 2-ClEE2 formed much less alkyl monohydroxylated metabolite (C-16 hydroxylated for 2-Cl- and 2-IEE2) than did either 2-BrEE2 or 2-IEE2. The observed structure-metabolism relationships are discussed.
