The usefulness of Øie-Tozer's model in deriving pharmacokinetic changes in response to changes in the concentration of drug-binding plasma protein.

1. Øie-Tozer's model can be used to derive changes in the distribution of drugs in relation to changes in the concentration of drug binding plasma proteins. 2. Concerns have been raised that the model is invalid for this purpose because it does not account for active drug transport, pH differences between fluids and extracellular tissue binding. 3. Here, it is demonstrated that these imperfections do not affect the outcome of the calculation.

The role of intramolecular self-destruction of reactive metabolic intermediates in determining toxicity.

When reactive centers are formed in chemical conversions, intermolecular reactions tend to dominate over intramolecular alternatives whenever both alternatives are possible. Hence, when reactive metabolites are formed from xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may play an important role in reducing toxicity related to reactive intermediates. The phenomenon is likely to be particularly noticeable for toxicophores that are readily associated with a type of toxicity that is rarely caused by other structural motives. In two demonstrative investigations, it is concluded that nitrobenzenes for which the expected nitrosyl metabolite is likely to react with adjacent groups are less toxic than what is rationally expected, and that among aryl amine drugs allowing for the immediate quenching of the corresponding N-aryl hydroxylamine metabolite, the typical erythrocyte toxicity often seen with aryl amines is absent. The deliberate introduction of effective quenching groups nearby a toxicophoric moiety may present a potential strategy for reducing toxicity in the design of drugs and other man-made xenobiotics.

The connection Between Plasma Protein Binding and Acute Toxicity as Determined by the LD50 Value.

Preclinical Research A dataset of three drug classes (acids, bases, and neutrals) with LD50 values in mice was analysed to investigate a possible connection between high plasma protein binding and acute toxicity. Initially, it was found that high plasma protein binding was associated with toxicity for acids and neutrals, but after compensating for differences in lipophilicity, plasma protein binding was found not to be associated with toxicity. The therapeutic index established by the quotient between mouse LD50 and the defined daily dose was unaffected by both lipophilicity and plasma protein binding.

The impact of the concentration of drug binding plasma proteins on drug distribution according to Øie-Tozer's model.

1. New equations have been developed from an updated version of Øie-Tozer's model expressing how the free concentration and volume of distribution change in relation to changes in the concentration of drug binding plasma proteins. This updated model accommodates more than one drug binding plasma protein to contribute to the plasma protein binding. 2. Demonstrations of the model show that variability in the concentration of one plasma protein has considerably less impact on the free drug concentration and volume of distribution if other plasma proteins contribute to binding, than if they don't.

How to report and discuss ADME data in medicinal chemistry publications: in vitro data or in vivo extrapolations?

Early drug discovery projects often utilize data from ADME (absorption, distribution, metabolism, elimination) assays to benchmark data and guide discussion, rather than the predicted in vivo consequences of these data. Here, the two paradigms are compared, using evaluations of metabolic stability based on either microsomal clearance assay data or from the predicted in vivo hepatic clearance and half-life calculated through the combination of the venous well-stirred model and Øie-Tozer's model. The need for a shift in paradigm is presented, and its implications discussed. It is suggested that discussions about ADME data should revolve around potential clinical problems that are most likely to surface during the development phase, each benchmarked with a suitable variable derived from the assay data.

Investigation of the prerequisites for the optimization of specific plasma protein binding as a strategy for the reduction of first-pass hepatic metabolism.

1. It is hypothesized that the deliberate structural tailoring of compounds designed for drug use to increase the specific plasma protein binding can be used to reduce first-pass hepatic metabolism. To test the feasibility of this hypothesis, a dataset of drugs with plasma protein binding of 90% or above divided into three classes including 50 acids, 44 bases and 69 neutrals was analyzed. 2. Among the drugs with ≥99% plasma protein binding, the fraction of the total dose existing in free form in vivo (free dose fraction) decreased in the following order: acids (0.55%) > neutrals (0.16%) > bases (0.08%). The order was different for the fraction of the total dose that existed in plasma protein bound form (plasma protein bound dose fraction): acids (58%) > neutrals (17%) = bases (18%). 3. The free fraction was poorly correlated with the partition coefficient (Log P). The lower aqueous solubility associated with high plasma protein binding was explained by differences in Log P and not by the plasma protein binding per se. The logarithm of the extrarenal clearance was correlated with Log P. For acids and bases, extrarenal clearance was also correlated with fu. For neutrals, plasma protein binding had no protective effect.

Visualization of plasma and tissue binding using dose fractions parameter.

A novel concept of dose fractions, based on the distribution of total bioavailable dose between the six combinations of location and binding state in Øie-Tozer's model is suggested as a way to visualize the distribution pharmacokinetics of a drug. The concept of dose fractions provides a sharper terminology in discussions of drug distribution allowing for a more precise description of the state and location of a drug within a system. In medicinal chemistry literature, the free fraction of a drug in plasma is a commonly discussed factor affecting the exposure to free drug while tissue binding is less well addressed. The free dose fraction, defined as the fraction of the bioavailable dose existing in free form, is suggested as a potentially valuable term for such discussions. Presently, drugs with high (>95%) plasma protein binding are viewed with skepticism, the rational behind which is questioned. The plasma protein bound dose fraction defined as the fraction of the total available dose, which is bound to plasma proteins, is suggested as a measure of the risk for problems related to fluctuations in free drug exposure due to variations in the concentration of drug binding plasma protein.

Net present value approaches for drug discovery.

Three dedicated approaches to the calculation of the risk-adjusted net present value (rNPV) in drug discovery projects under different assumptions are suggested. The probability of finding a candidate drug suitable for clinical development and the time to the initiation of the clinical development is assumed to be flexible in contrast to the previously used models. The rNPV of the post-discovery cash flows is calculated as the probability weighted average of the rNPV at each potential time of initiation of clinical development. Practical considerations how to set probability rates, in particular during the initiation and termination of a project is discussed.

Rational Drug Design Leading to the Identification of a Potent 5-HT(2C) Agonist Lacking 5-HT(2B) Activity.

The 5-HT(2C) receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT(2C) receptor agonists. After expanding our structure-function library, we were able to combine our datasets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT(2B)/5-HT(2C) agonists, which has led to the identification of a highly selective 5-HT(2C) agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC(50) of 55 nM and no detectable agonism at the 5-HT(2B) receptor.

Microwave-accelerated spiro-cyclizations of o-halobenzyl cyclohexenyl ethers by palladium(0) catalysis.

A number of new spiro[cyclohexane-1,1'-isobenzofuran]-based compounds was synthesized by palladium(0)-catalyzed 5-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to promote both product yield and reaction rate without compromising the selectivity. Heck cyclization of aryl iodide 6, 2-(2-iodobenzyloxy)cyclohex-2-enyl acetate, proceeded selectively without involvement of the allylic acetate functionality.

A one-pot isomerization-arylation of 2,3-epoxycyclohexanone under controlled microwave heating.

A fast one-pot method has been developed for the direct preparation of 3-aryl-1,2-cyclohexanediones from 2,3-epoxycyclohexanone via a microwave-assisted tandem epoxy ketone isomerization-Heck arylation reaction. The preparative microwave-assisted reactions were performed preferentially in 50% aqueous poly(ethylene glycol) utilizing sodium acetate as the base. Within 5-30 min of directed microwave heating, employing less than 0.05 mol % of palladium acetate and no phosphine ligand, up to 72% yield of C3-arylated diketones was isolated in an overall environmentally benign process. On the basis of the chemical reactivity of proposed intermediates, a reaction pathway is proposed where the acetate base promotes the rearrangement of the 2,3-epoxycyclohexanone into the active mono-enol form of 1,2-cyclohexanedione. An alternative classically heated procedure for isomerization-C3-arylation of 2,3-epoxycyclohexanone in DMF is also reported.

Microwave-promoted and chelation-controlled double arylations of terminal olefinic carbon of vinyl ethers.

Herein we report a rapid, palladium-catalyzed terminal diarylation of the chelating olefin N,N-dimethyl(2-ethenyloxy)ethanamine under noninert conditions utilizing controlled microwave heating as a convenient energy source. Among the aryl bromides examined, both electron-rich and electron-poor substrates were demonstrated to furnish useful yields after only 10-120 min of directed microwave heating at 160-200 degrees C. The good terminal regioselectivity suggests that the precatalyst (Herrmann's palladacycle) serves as a source of weakly coordinated palladium(0) in the investigated high-temperature Heck process.