Prodrugs and Drug Like Properties

Many have used the following scheme (Scheme 1) to describe the prodrug approach to the delivery of problematic molecules.

Derivatization

Transformation

Scheme 1. An illustration of the prodrug concept.

Scheme 1. An illustration of the prodrug concept.

Prodrugs are chemical modifications of drug or potential drug molecules used to overcome barriers to the efficacy, deliverability and utility of problematic molecules. The barrier shown in the scheme can include but is not limited to;

• low water solubility leading to compromised oral, dermal. ophthalmic and parenteral delivery

• high polarity leading to poor cellular permeability

• poor chemical and metabolic stability leading to presystemic metabolism and short biological residence times

• lack of site of action targeting leading to high side effects and compromised pharmacodynamics (PD)

• compromised physicochemical properties leading to patient acceptability and formulability issues

• poor intellectual property right protection leading to the lack of economic incentive

Ferres (1983) has used Scheme 2 to illustrate the possible advantages of the prodrug solution compared to an analog approach

In this scheme, the delivery problems could be overcome without compromising receptor activity since the active species remains with the analog or what has been referred to in the prodrug literature as the parent molecule or parent drug. A significant number of recently marketed molecules are prodrugs (about 14% at small molecule NCEs approved worldwide in 2001and 2002) yet the use of prodrugs to address solutions to the formulation and delivery of problematic drugs was often disdained in both big pharma as well as in emerging companies. This appears to be changing. Having consulted for the pharmaceutical industry for the last 32 years on a number of issues including the use of prodrugs, I have drug analog prodrug drug analog prodrug

RECEPTOR RECEPTOR RECEPTOR no activity non-fit activity

Scheme 2. . Illustration used by Ferres (1983) to show the potential differences between an analog and a prodrug approach to drug receptor activity. Reproduced with permission (Ferres, 1983).

had more requests to give talks and to consult on the possible use of prodrugs as a problem solving technique in the last two to three years than in my previous 30 years. The basis for some of this increased interest is discussed in some recent publications (Krise and Stella, 2003; Stella, 2004). The number of prodrug patents has increased dramatically in the last 10 years (2000% increase over 1993, see Figure 1) and the number of recently approved drugs that are in fact prodrugs strongly suggest that prodrug strategies are becoming an integral part of the drug discovery paradigm (Stella, 2004). Drug discovery teams seem to be raising the idea of the use of prodrugs earlier rather than as an afterthought.

Year

Figure 1. Plot of the number of patents per year over the last 10 years from a search using the terms, prodrugs, drug latentiation, bioreversible derivatives and ADEPT ( Stella, 2004). The number of patents for 2003 was only estimated from the numbers collected over approximately the first half of the year.

Year

Figure 1. Plot of the number of patents per year over the last 10 years from a search using the terms, prodrugs, drug latentiation, bioreversible derivatives and ADEPT ( Stella, 2004). The number of patents for 2003 was only estimated from the numbers collected over approximately the first half of the year.

Professor Adrian Albert, the author of the term pro-drug or pro-agent, spoke eloquently of the topic of this workshop in his book, "Selective Toxicity" in the 1950s (see Albert, 1985). He recognized the often disconnect between receptor binding and receptor access so suggesting the prodrug approach as a means of overcoming the gap. Have we really come a long way since the 1950s?

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