Oral availability

An impressive example of the application of structure-based methods was the design of a inhibitor of the HIV protease by a group of scientists at DuPont Merck [Lam et al. 1994 This enzyme is crucial to the replication of the HIV virus, and inhibitors have bee shown to have therapeutic value as components of anti-AIDS treatment regimes. The star1 ing point for their work was a series of X-ray crystal structures of the enzyme with number of inhibitors boimd. Their objective was to discover potent, novel leads whid were orally available. Many of the previously reported inhibitors of this enzyme possessei substantial peptide character, and so were biologically unstable, poorly absorbed am rapidly metabolised. 

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

The antiepileptic drug phenytoin, an orally available class DB antiarrhythmic, is mainly effective in digitalis-induced arrhythmias. This diug exhibits nonlinear pharmacokinetics and a number of side effects including neuropathy, gingival hypetplasia, hepatitis, immunological disorders and suppression of white blood cells. 

Founmer, F., Karasow, W.H., and Kenow, K.P. et al. (2002). The oral availability and toxicokinetics of methyl mercury in common loon chicks. Comparative Biochemistry and Physiology, Part A 133, 703-714. 

LOWN K S, BAILEY D G, FONTANA R J, JANARDAN S K, ADAIR C H, FORTLAGE L A, BROWN M B, GUO w, WATKINS p B (1997) Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest. 99 2545-53. 

Preterm labour is the major cause of perinatal morbidity and mortality. Oxytocin antagonists offer an attractive approach to prevention. Chapter 7 reviews three decades of medicinal chemistry in this field. The peptide approach has resulted in valuable injectable products. Selectivity over the related vasopressin receptors and improvement in pharmacokinetic profile have been the key challenges for more recent non-peptide programmes, and these seem likely to yield orally available medicines. 

Lomustine is an orally available nitrosurea alkylating agent. Lomustine is converted rapidly to the cis- and frans-4-hydroxy metabolites the range of half-lives of these two metabolites is 2 to 4 hours.25 Lomustine has shown clinical activity in the treatment of Hodgkin s lymphoma and melanoma. Side effects are similar to those of carmustine. Patients should receive only enough drug for one cycle at a time to prevent confusion and accidental overdose. 

Morokata T, Suzuki K, Masunaga Y, et al. A novel, selective, and orally available antagonist for CC chemokine receptor 3. J Pharmacol Exp Ther 2006 317(l) 244-250. 

P Schmeidlin-Ren, DJ Edwards, ME Fitzsimmons, K He, KS Lown, PM Woster, A Rahman, KE Thummel, JM Fisher, PF Hollenberg, PB Watkins. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 25 1228-1233, 1997. 

The screening of permeability coefficients for orally available drugs in the LI phase can be made with the intention to ... 

K. S., Woster, P. M., Rahman, A., Thummei, K. E., Fisher, J., Hollenberg, P. F., Watkins, P. B., Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit juice constituents, Drug Metab. Disp. 1997, 25, 1228-1233. 

The number of publicly available datasets with reasonable quality of data is quite limited. In this part of the chapter, we will list datasets related to intestinal absorption and oral availability, and of which we are aware at the present time. 

One of the major goals of computational chemistry in the field of drug metabolism and pharmacokinetics (DMPK) is the prediction of oral availability. Several computational approaches have been published to predict this important parameter, starting from the molecular structure [1-3]. However, when applied to real case studies, none of these provided totally convincing results and, correspondingly, there is a lack of any general strategy to address this problem. 

Oral availability is a complex parameter that involves several chemical and physiological processes such as solubility, chemical stability, permeability and first-pass metabolism, to mention a few. All of these subprocesses depend on two different types of factor (i) interaction of the drug compound with certain macromolecules, such as the metabolism mediated by the cytochromes P450 family and (ii) interaction of the drug molecule with a certain chemical or biological environment, that will determine the solubility or the passive permeability. 

Each subprocess can be the cause of a poor oral availability or, vice versa, a poor oral availability can be due to several different reasons. Therefore, we are truly convinced that the ah initio prediction of oral availability as such, without considering the impact of the other physico-chemical processes, is still impossible. 

To date, however, present several computational approaches have been reported to predict the important subprocesses for oral availability. This chapter will present some examples for the prediction of such pharmacokinetic properties, starting from the three-dimensional (3D) structure of the drug candidates. In our experience it is much better to develop and use a number of different simple local models, than to use a unique complex model that depends on a multitude of poorly understood subfactors. 

Inhibitors of MLK (MKKK) [27], MKK4, 7 and JNK [6,28,29] have been disclosed to date. CEP-1347, a semi-synthetic analog of the natural product K252a, inhibits MLKs in the JNK pathway with K = 17 nM [30-32]. This compound has shown neuroprotective effects in cellular and animal models [33]. CEP-1347, an orally available compound that was well tolerated in the clinic, was advanced to Phase II/III trials for assessing efficacy in Parkinson s disease. However, the clinical trial was stopped due to a lack of significant efficacy [34],... 

The pharmacological properties of 108 are not ideal. It removes iron only slowly and it is not well absorbed by oral administration so it has to be administered by injection. Therefore there is need for new chelators. The orally active chelator l,2-dimethyl-3-hydroxypyridin-4-one (LI) 109 is on clinical trial for the treatment of thalassemia (543). Several other chelators which contain 3-hydroxy-4(H)-pyridinone such as 110-112 also possess oral availability, and have comparable activity to 109 for the removal of iron from the liver (544, 545). These... 

J. D. Allen, S. C. Van Dort, M. Buitelaar, O. van Tellingen, and A. H. Schinkel. Mouse breast cancer resistance protein (Bcrpl/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res 63 1339-1344 (2003). 

The highly polar clodronic acid (9.53, R, R = Cl), etidronic acid (9.53, R = Me, R = OH), and a number of analogues have demonstrated their clinical value in the treatment of osteoporosis, but they must often be administered by slow intravenous infusion due to their poor oral bioavailability. Esterification to orally available prodrugs is, thus, an actively investigated strategy. Promising results have, for example, been obtained with (pivaloyl-oxy)methyl esters of clodronic acid [120]. 

---