Pharmaceuticals discovery

Gardner SP, Flores TP. Integrating information technology with pharmaceutical discovery and development. Trends Biotechnol 1999 18 2-5. 

Some of the compUcations Usted above could be flagged and, sometimes, remedied in a manual shake-flask experiment, but that is unlikely to be the case in automated shake-vial procedures, especially if performed in a 96-well plate setting. Nevertheless, the demands of modern pharmaceutical discovery operations emphasize high-throughput measurements, low compound consumphon... 

Pharmaceutical discoveries are principally made by thoughtful structural variation on a lead compound which has been found, by chance or design, to have a certain amount of the desired activity. It is clear that with metalloporphyrins, there are additional structural variations to be had. In the first place, it is possible to vary the metal. It was realized at an early stage that inserting and varying the metal would modify PDT activity.61 The possibility also exists of structural changes in axial ligands in those metalloporphyrins which possess them. This structural variation occurs in the space immediately above and below the macrocycle, which is a space not readily accessible to controlled variation in metal-free compounds of this series. 

I express great appreciation to Drs. John Barrett and Paul McGuirk (Pfizer Central Research) and Dr. Linus Shen (Abbott Pharmaceutical Discovery) for their expert opinions, comments and suggestions concerning this review. 

Fig. 2.2 Attrition rate in the current pharmaceutical discovery protocol. These estimates are for illustrative purposes exact figures are difficult to average across the industry, as most companies do not disclose screening success/failure rates. Modified from [12] with permission.

Borchardt, R.T., Freidinger, R.M., Sawyer, T.K., Smhh, P.L. (eds.) Integration of Pharmaceutical Discovery and Development Case Histories. Plenum Press, New York, 1998. 

P. A. Wabnitz, J. A. Loo Drug screening of pharmaceutical discovery compounds by micro-size exclusion chromatography/mass spectrometry. 

Due to the advantages offered by AS-MS, it can be anticipated that these techniques will be increasingly applied by medicinal and synthetic organic chemists, biochemists, analytical chemistry experts and other researchers throughout the pharmaceutical discovery community. 

Natural products, thus, have been the major sources of chemical diversity as starting materials for driving pharmaceutical discovery over the past century.Many natural products and synthetically modified... 

Lombardo F, Winter SM, Tremain L, Lowe III JA, In Integration of Pharmaceutical Discovery and Development ... 

In conclusion, we find that although some periods of time are likely to result in more productive discoveries than others, there is no evidence that gains from pharmaceutical discovery have been fiilly realized. To the contrary, it is likely that as valuable new pharmaceutical products are introduced, and drugs made more accessible to broader populations, further improvements in life expectancies will result. 

Pharmaceutical Discovery Division, SRI International, Menlo Park, CA, USA michael. groziak sri. com... 

Borchardt, R.T., Integration of pharmaceutical discovery and development case histories. Pharmaceutical biotechnology v. 11. 1998, New York Plenum Press, xxix, 607. 

Yamell, E. 2000. The botanical roots of pharmaceutical discovery. Alternative Complementary Therapies. June 2000, p. 125-128. 

A composition based on diketopiperazine derivatives (3,6-bis (N-fumaryl-N-(n-butyl) amino-2, 5-diketopiperazine) has been investigated as a pulmonary drug delivery system, termed Technospheres (Pharmaceutical Discovery Corp., Elmsford, NY) (Pohl et al. 2000 Steiner et al. 2002). The diketopiperazine derivatives self-assemble into microparticles at low pH with a mean diameter of approximately 2 pm. During self-assembly, diketopiperazine derivatives microencapsulate peptides present in the solution. Insulin incorporated in diketopiperazine derivatives (TI) was administered to five healthy humans by the use of a capsule-based inhaler with a passive powder deagglomeration mechanism. Relative and absolute bioavailability of TI in the first 3 hours (0-180 min) were 26 12% and 15 5%, and for 6 hours (0-360 min) 16 8% and 16 6%, respectively (Steiner et al. 2002). The time to peak action for glucose infusion rates was shorter with both IV (14 6 min) injection and inhalation (39 36 min), as compared to SC administration (163 25 min). This rapid absorption of insulin would be beneficial for diabetic patients who need to rapidly affect their glucose levels. 

Carbocyclic rings, unlike saturated heterocyclic rings, are not susceptible to the hepatic activation that is the basis of much drug toxicity. To pave the way for pharmaceutical discovery based on carbocyclic agents, much effort is going into the development of practical procedures for their stereocontrolled construction. 

The Integration of Structure-Based Design and Directed Combinatorial Chemistry for New Pharmaceutical Discovery... 

From a pharmaceutical discovery perspective, it could be fruitful to embark on a library synthesis using cyclic hydroxamic acid templates. There are several reports describing interesting bioactivities for such compounds, particularly as inhibitors of metal-dependent enzymes 48-52 However, only three a-mercapto acid monomers are currently available from commercial sources hence the structural diversity of products that could be easily prepared is limited. Several approaches to introducing additional points of diversity into the benzothiazinone scaffold are currently under investigation. 

Whereas 2D databases of compounds play an invaluable role in pharmaceutical discovery research, a computational chemistry calculation on a molecule often requires its 3D structure. An excellent starting point for such a calculation is sometimes one of the molecules in the Cambridge Structural Database (CSD), a 3D database. The CSD (24-26) presently has atomic co-ordinates and other information for over 300,000 small organic and organometallic compounds, most of which have been solved by x-ray crystallography. The number of structures in the database is growing by about 10%... 

Cepa, S. Searle, P. 1998. Establishing an open access LC/MS lab for pharmaceutical discovery and development. Proc. 46th ASMS Conf. Mass Spectrom. and Allied Topics (Orlando, Florida), 283. 

M. Weatherall, In Search of a Cure, a History of Pharmaceutical Discovery, Oxford University Press, Oxford, 1990. 

---