Aqueous lead optimization

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

Lead optimization of a series of oxazolidinone derivatives led to the discovery of rivaroxaban l.9 Basic screening tests for this compound demonstrated a highly potent and selective, direct inhibitory action on FXa (IC o = 0.7 nM, Kj = 0.4 nM), excellent in vivo antithrombotic activity and a good pharmacokinetic profile in preliminary studies in animal models (Table 1). The lipophilic chlorothiophene moiety in rivaroxaban is responsible for a decrease in unbound fraction and aqueous solubility and attempts to identify less lipophilic replacements by broad variation were not successful. 

Aqueous Solubility in Lead Identification and Lead Optimization... 

Aqueous Solubility in Lead identification and Lead Optimization 19... 

Aqueous Solubility in Lend Identification and Lead Optimization 25... 

P3 [31,33]. These modifications were introduced during lead optimization to improve aqueous solubility and potency by limiting the conformational freedom of the inhibitor. The transition from the heptapeptide starting point to the marketed drug saquinavir is indicated in Figure 7.2. The central transition-state mimic is indicated in blue. 

Precipitation is affected by pH, solubiUty product of the precipitant, ionic strength and temperature of the aqueous stream, and the presence of metal complexes. For each metal precipitant, there is an optimum pH where its solubiUty is lowest and hence, the highest removals may be achieved. When an aqueous stream contains various metals, the precipitation process caimot be optimized for each metal, sometimes making it difficult to achieve effluent targets for each. SolubiUty products depend on the form of the metal compound and ate lowest for metal sulfides, reflecting the relative insolubiUty of these compounds. For example, the solubiUty product for lead sulfide [1314-87-0] is on the order of compared to 10 for lead carbonate. Metal... 

The formation of colloidal sulfur occurring in the aqueous, either alkaline or acidic, solutions comprises a serious drawback for the deposits quality. Saloniemi et al. [206] attempted to circumvent this problem and to avoid also the use of a lead substrate needed in the case of anodic formation, by devising a cyclic electrochemical technique including alternate cathodic and anodic reactions. Their method was based on fast cycling of the substrate (TO/glass) potential in an alkaline (pH 8.5) solution of sodium sulfide, Pb(II), and EDTA, between two values with a symmetric triangle wave shape. At cathodic potentials, Pb(EDTA)2 reduced to Pb, and at anodic potentials Pb reoxidized and reacted with sulfide instead of EDTA or hydroxide ions. Films electrodeposited in the optimized potential region were stoichiometric and with a random polycrystalline RS structure. The authors noticed that cyclic deposition also occurs from an acidic solution, but the problem of colloidal sulfur formation remains. 

In aqueous DMF, the reaction can be applied to the formation of C-C bonds in a solid-phase synthesis with resin-bound iodobenzoates (Eq. 6.33).80 The reaction proceeds smoothly and leads to moderate to high yield of product under mild conditions. The optimal conditions involve the use of 9 1 mixture of DMF-water. Parsons investigated the viability of the aqueous Heck reactions under superheated conditions.81 A series of aromatic halides were coupled with styrenes under these conditions. The reaction proceeded to approximately the same degree at 400°C as at 260°C. Some 1,2-substituted alkanes can be used as alkene equivalents for the high-temperature Heck-type reaction in water.82... 

Aqueous solubility, potency and permeability are three factors under medicinal chemistry control that must be optimized to achieve a compound with acceptable oral absorption. Typically, a lead (chemistry starting point) is deficient in all three parameters. The inter-relationships of these three parameters has been described in a series of publications from Pfizer researchers [7, 8]. Figure 9.1 depicts graphically the minimum acceptable solubility as a function of projected clinical potency and intestinal permeability. A minimum thermodynamic aqueous solubility of 52... 

The pH of a metalworking fluid must be kept above neutrality in order to prevent acid corrosion of the metal In vitro, acid catalyzed nitrosation is optimized at pH 3.5 (4 0) however, it has been shown that In the presence of other catalysts, aqueous solutions of amines and nitrite leads to significant yields of nitrosamines at room temperature over the pH range of 6.4 to 11.0 (41). Furthermore, C-nitro-containing, formaldehyde-releasing biocides, such as bronopol or tris nitro, exert their potential catalytic effect in alkaline solution. It would thus be desirable to determine the optimum pH for a metalworking fluid that would lead to the lowest concentration of nitrosamine possible. 

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