Biomedical Engineering Reference
In-Depth Information
GABA
A
receptors. Gaboxadol is a clinically active nonopioid analgesic and a nonbenzodiazepine
hypnotic, which at present is in clinical trials (see also Chapters 15 and 20).
The angiotensin-converting enzyme (ACE) is a zinc carboxypeptidase centrally involved in the
regulation of blood pressure and is an important target for therapeutic intervention. Peptide toxins
from the Brazilian pit viper,
Bothrops jararaca
and the synthetic peptide analogue, teprotide, are
inhibitors of ACE (Figure I.4), but are not suitable for therapeutic use. Systematic molecular dis-
section of teprotide led to the nonpeptide ACE inhibitor,
N
-succinylproline, which was converted
into the structurally related and much more potent analogue, Captopril that is now marketed as an
effective antihypertensive drug.
I.5.3 B
ASIC
P
RINCIPLES
IN
L
EAD
D
EVELOPMENT
AND
O
PTIMIZATION
Potency, efi cacy, and selectivity are essential but certainly not the only parameters to fuli ll for a
pharmacologically active compound to become a therapeutic drug. A large number of additional
requirements have to be met, the most important of which have been summarized in the acronym,
ADME (Section I.4), which actually should be extended to ADME-Tox (ADME as well as toxicity).
Obviously, the drug must reach the site of action in a timely manner and in sufi cient concentration
to produce the desired therapeutic effect.
After oral administration, the drug must survive the acidic environment of the stomach. In the small
intestine, the bulk of absorption takes place. Here, the pH is neutral to slightly acidic. In the gastro-
intestinal system metabolism can take place. The presence of digestive enzymes creates particular
problems for polypeptide drugs, and the gut wall is fairly rich in oxidative enzymes.
Unless the drug acts as a substrate for active energy-requiring uptake mechanisms, which nor-
mally facilitate uptake of, for example, amino acids and glucose, it must be signii cantly unionized
to penetrate into the body. Following absorption, the blood rapidly presents the drug to the liver,
where Class I metabolic transformations (oxidation, hydrolysis, reduction, etc.) and in some cases
Phase II transformations (glucuronidation, sulfatation, etc.) take place. The polar reaction products
from these reactions are then typically excreted in the urine or feces.
The rate of absorption of drugs, their degree of metabolic transformation, their distribution in
the body, and their rate of excretion are collectively named pharmacokinetics. This is in effect the
inl uence of the body on a drug as a function of time. The interaction of the drug with its receptors,
in the broad sense of the word, and the consequences of this interaction as a function of time are
pharmacodynamics.
Both of these characteristics are alone governed by the drug's chemical structure. Thus, the
medicinal chemist is expected to remedy any shortcomings by structural modii cations. In addition
to ADME-Tox, a number of other characteristics must also be satisfactory, such as:
•
Freedom from mutagenesis
•
Freedom from teratogenecity
•
Chemical stability
•
Synthetic or biological accessibility
•
Acceptable cost
•
Ability to patent
•
Clinical efi cacy
•
Solubility
•
Satisfactory taste
•
Ability to formulate satisfactorily for administration
•
Freedom from idiosyncratic problems
These challenges emphasize the key importance of scientists trained in interdisciplinary medicinal
chemistry in drug discovery and development projects.
