Improved Pharmacokinetics

The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

T-1249 demonstrated substantial activity against enfuvirtide-resistant viruses in clinical studies (Melby et al. 2007a) however, development was discontinued due to formulation issues. Additional peptides with more potent activity were subsequently designed, which also showed much improved pharmacokinetic properties (Dwyer et al. 2007) however, the availability of oral agents in other new classes makes the likelihood of the development of these agents uncertain. 

In order to overcome the limitations of the above drugs, a series of rifamycin derivatives with improved pharmacokinetic (i.e. virtually absence of GI absorption) and pharmacodynamic (i.e. with broad spectrum of antibacterial activity) properties have been synthesized at Alfa Wassermann laboratories [33]. Amongst the different molecules, the compound marked L-105 and later... 

Cyclic ureas incorporating a 1,3-diazepinone skeleton continue to be of pharmacological interest. The Ai V-disubstituted system 89 has been prepared and shown to be a potent inhibitor of factor Xa in vitro and to have an improved pharmacokinetic profile in the rabbit. The binding model for this series of compounds was confirmed by an X-ray crystallographic analysis of one analogue in the series <00BMCL301>. 

Most interestingly, phthalamate analogues 21-23 were identified as potentially new pTyr mimics that may yield inhibitors equipotent to pTyr-containing compounds with the advantage of improved pharmacokinetic profiles. 

Innovation on formulations to improve pharmacokinetics (see Table 1) is a common strategy to address the generic introduction of zolpidem (2007 in the US). 

Aminopyrrolidinone farnesyltransferase inhibitors design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. Journal of Medicinal Chemistry, 45, 2388-2409. 

Since the discovery of penicillin, research has produced a large number of different types of derivatives with the aim to extend antibacterial activity and to improve pharmacokinetic properties [1][2],... 

The above examples illustrate the versatility and overlapping substrate specificities of peptidases, but they also serve to explain the difficulties faced by medicinal chemists who try to design bioactive peptides that have improved pharmacokinetic properties. Clearly, general predictive rules and a global understanding of the in vivo fate of peptides are not in sight, but the sections below will show that medicinal chemists have developed various successful strategies of a rather empirical nature [7][181-188],... 

A first and apparently straightforward strategy to improve pharmacokinetic behavior of bioactive peptides is to derivatize the N-terminus, the C-terminus, and/or one or more functionalized side chains. Different biological consequences are conceivable depending on the stability and intrinsic activity of the derivative. 

A few modem nitrovasodilators have been designed and developed to improve pharmacokinetic properties. Two examples discussed below are (6-chloropyridin-2-yl)methyl nitrate and trans-2-amino-2-methyl-./V-[4-(nitro-oxy)cyclohexyl]propanamide. 

Brange, J. Volund, A. Insulin analogs with improved pharmacokinetic profiles. Adv. Drug Deliv. Rev. 1999, 35, 307-335. 

By using recombinant DNA techniques, modifications in the protein backbone, such as additions, deletions and alterations of amino acids, are easily achieved. These modifications can contribute to improved pharmacokinetic properties of the construct. Additions may consist of the introduction of residues that allow covalent conjugation of drug molecules. Deletions of amino acids can employed to remove membrane-bound regions of a protein, thereby increasing its solubility. Single amino acid modifications can be used to minimize antibody responses and alter the binding specificity and/or the three-dimensional structure of a certain protein. 

Beside the actual steric bulk of the substituent, cyclopropyl is much more stable to hydrogen abstraction than other alkyl functions and represents an ideal terminal group. These changes make betaxolol a compound with much improved pharmacokinetics compared to its lipophilic analogues. 

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