INTRODUCTION:

Lead optimization is the complex, non linear process of refining the chemical structure of the confirmed hit to improve its drug characteristic with the goal of producing a preclinical drug candidate. This stage frequently represents the bottleneck of the drug discovery program. The lead optimization process is highly interactive¹. Leads are assessed in pharmacological assays for their “druglikeness”. Typically, one or more confirmed hits are evaluated in the secondary assays, and a set of related compounds. Called analogs, are synthesized and screened^2.

LEAD OPTIMIZATION-ANIMAL PK/ PD/ ADME:

Animal pharmacokinetics (PK), pharmacodynamics (PD) and absorption distribution, metabolism and extraction (ADME) assess the general pharmacology and mechanism of action of drugs^3.

Lead molecules are administration via different routes: Intravenous (iv), intraperitoneal (ip), subcutaneous (sc), intramuscular (im), rectal, intranasal (in), inhalation, oral, transdermal, topical etc. The main models used are rodents including mouse and rats, but larger animals such as dogs, pigs and many more rarely monkeys are also used under certain circumstances.

The main objective is to understand the effects on the whole organisms of exposure to a novel chemical entity, and to predict the new drugs behavior in the humans⁴.

PK/PD/ADME studies are an integral part of lead optimization. They feed back into the medicinal chemistry effort aiming to optimize the physicochemical properties of new lead in terms of minimal toxicity and side effects, as well as of maximum efficacy towards diseases⁵.

PK/ PD/ ADME studies are expensive and usually have limited throughput. Some PK/PD studies require specific formulations, pro-drugs or radioisotope labeling of lead molecules, all of which tend to draw heavily on medicinal chemistry resources⁶.

PK/PD/ADME studies innovation and progress in mass spectroscopy, (whole body) imaging and chromatography technology (HPLC, LC-MS, LC-MS-MS) have tremendously increased the quantity and quality of data generate in PK/ PD experiments^7,8.

A large number of parameters are assessed. Here is a partial list: ADME; bioavailability (F) and protein binding; stability and half life(t_1/2); maximum serum concentration (Cl); volume of distribution; drug-drug interactions; onset of drug action; multi compartmental analysis of blood, liver and other tissues⁹.

LEAD OPTIMIZATION-TOXICITY:

The definition of toxicity is the degree to which a substance or mixture of substance can harm human and animal. Acute toxicity involves harmful effects over an extended period, usually upon repeated or continuous exposure that can last further entire life of the exposed organism. These may well applied to many Alzheimer’s drugs¹⁰.

The screening includes a series of standard assays early on: P450 inhabitation (using either recombinant cytochrome P450 enzymes or liver micro some), MTT like cytotoxicity assays, effects on cardiac HERG channels. Toxicity in these relatively simple in vitro assays flags hits or lead and goes into the risk- benefit evaluation of which leads series can advance into preclinical studies¹¹.

Animal models are used for the escalating dose studies aimed at determining the maximum tolerated dose (MTD). This step involves monitoring a series of parameters such as bodyweight, food intake, blood chemistry and liver activity. Biopsies are usually stored in freezers for subsequent pathological analysis¹².

Animal toxicity studies require relativity large amounts of compound. The purity of the compound needs to be very high in order to exclude toxicities stemming from impurities. The norm for short term animal toxicity is one or two week studies. Long term testing in animal ranges in duration from several weeks to several years. Some animal testing continues after human tests have begin in order to learn whether long- term use of a drug may causes cancer or birth defects¹³.

LEAD OPTIMIZATION-FORMULATION AND DELIVERY:

The formulation and delivery of drugs is an integral part of the drug discovery and development process. Indeed, formulation problem and solution influence the design of the lead molecules; they feed back into the iterative lead optimization cycle, as well as the preclinical and clinical evaluation¹¹. In turn, formulation and delivery are closely linked. For example, intravenous delivery of noble drugs might call for the different formulation than oral delivery, because parameters such as metabolic stability or solubility can differ significantly.

If the formulation substances are not generally recognizes as safe, they become part of the safe assessment and their PK/PD/ ADME behavior, as well as toxicity profile, needs to be documented in the IND (investigational new drugs) application. In fact, sides effect such local irritation or allergic reactions are often attributable to drug formulation, not the active pharmaceutical ingredient (API)¹⁴.

Formulation substances might exhibit different biological activity than actual drug. For example, certain formulation enhance absorption through there interaction with the cell membrane of the gastrointestinal tract.

Formulation and delivery is highly specialized field of research, and formulation scientist is now part of serious drug discovery and development programs from the early stages¹².

Indeed, a sizable number of drug discovery and development programs in the pharmaceutical industry are centered around new ways of formulation already known and even marketed drugs to increases their efficacy or safety profiles.

CONCLUSION:

Lastly, medicinal chemists can change the lead molecules based on these results in order to optimize pharmacological properties such as bioavailability or stability. At that point, the new analogs feed back into the screening hierarchy for the determination of potency, selectively and MOA. These data then feed into the next optimization cycle. The medicinal chemistry combines empirical knowledge from the structure- function relationship of known drugs with rational design optimizing the psychochemical properties of the drug molecules. The lead optimization process continues for as long as it takes to achieve a defined drug profile that warrants testing of the new drug in humans.

REFERENCES:

1. Haden, J.S. The industrialization of drug discovery; Drug Discovery today, 7.2002 edition, pp 83-85.

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3. Rang H.P, Dale MM. and Ritter J.M (1999): Pharmacology, Churchill Livingstone, London, 4^th edition, pp 283-293.

4. Tripathi K.D (2003): Essential of medical pharmacology, Jaypee Brothers Medical Publication (Pvt) Ltd, New Delhi, 5^th edition.

5. Olin B.R., Hebel S.K, Dombek C.E., Drug Facts and Comparisons. 2007 edition. pp57.

6. Simon C., Everitt H, Kendrick T. Oxford Handbook of General Practice. 2^nd edn.Oxford: Oxford University Press, 2007: pp324-325.

7. Willard H.H , Merritt L.L., Dean J.A., Settle F.A. Instrumental Method of Analysis , CBS Publishers and Distributors, New Delhi, 1990 edition, pp 127.

8. Chatwal G and Anand S. Instrumental Method of the Chemical Analysis, Himalaya Publishing House, Delhi, 1995 edition , pp181.

9. Dipiro J.T., Talbert R.L., Yee G.C and Matzke G.R (1999): Pharmacology a pathophysiology approach, Connecticut: Appleton and Lange, 4th edition, pp141-142.

10. Katzung B.G (1995): Basic and Clinical Pharmacology, Prentice Hall International (UK) Ltd., London, 6^th edition, pp276-279.

11. Devlin, T. (1995): Textbook of biochemistry with clinical correlations, New York, Wiley-Liss Inc., 3^rd edition, pp376-381.

12. Bolten B.M., De Gregorio T; Trends in development cycles; Nature reviews drug discovery 1; 2002; pp335-336.

13. Hardman J.G, Limbird L.E. (1996): Goodman and Gilman^’s the pharmacological basis of therapeutics, New Delhi: McGraw Hill, Health Professions Divisions, 9^th edition, pp211.

14. Jagadeesh G; Angiotensin II receptors antagonists, molecular biology and signal transduction; Indian J. Experimental Biology. 1998; 36pp1171-1194.

Received on 23.12.2010 Modified on 10.01.2011

Asian J. Research Chem. 4(4): April, 2011; Page 509-510