The role of the medicinal chemist in drug discovery - Then and now

Nature Reviews Drug Discovery

Volumn 3, Issue 10, 2004, Pages 853-862

  Lombardino, Joseph G ^a   Lowe III, John A ^b  

^a Pfizer Inc ^*  (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 HYDROXY 2 METHYL N PHENYL 2H 1,2 BENZOTHIAZINE 3 CARBOXAMIDE 1,1 DIOXIDE; ACETYLSALICYLIC ACID; AMPHETAMINE; ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; APOMORPHINE; ASTEMIZOLE; ATYPICAL ANTIPSYCHOTIC AGENT; CARBOXYLIC ACID DERIVATIVE; CHLORDIAZEPOXIDE; CHLORPROMAZINE; CLOZAPINE; DICLOFENAC; DRUG; GENERIC DRUG; HALOPERIDOL; IBUPROFEN; IMATINIB; INDOMETACIN; NEUROLEPTIC AGENT; PHOSPHOTRANSFERASE INHIBITOR; PIROXICAM; PROTEIN FARNESYLTRANSFERASE INHIBITOR; SUDOXICAM; UNCLASSIFIED DRUG; ZIPRASIDONE;

ARTHRITIS; CHEMISTRY; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; COMBINATORIAL CHEMISTRY; CREATIVITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG FATALITY; DRUG INDUSTRY; DRUG MECHANISM; DRUG METABOLISM; DRUG RESEARCH; DRUG SYNTHESIS; EXPERIENCE; EXTRAPYRAMIDAL SYMPTOM; HISTORY OF MEDICINE; HUMAN; MEDICAL TECHNOLOGY; MODEL; NONHUMAN; ORGANIC CHEMISTRY; PRIORITY JOURNAL; REVIEW; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION; TOXICITY TESTING;

CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; EUROPE; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; LABORATORY PERSONNEL; PHARMACEUTICAL PREPARATIONS; UNITED STATES;

EID: 6444234760     PISSN: 14741776     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrd1523     Document Type: Review

References (30)

1. R&D execs paint bleak picture of industry productivity: $1.4 bil. per NME. The Pink Sheet 6 (18 August 2003).
2. Demesmaeker, M. in Proc. 13th European Symp. Quantitative Structure-Activity Relationships: Rational Approaches to Drug Design (eds Hoeltje, H.-D. & Sippl, W.) 506-511 (Prous Science, Barcelona, 2000).
3. Chanda, S. K. & Caldwell, J. S. Fulfilling the promise: drug discovery in the post-genomic era. Drug Discov. Today 8, 168-174 (2003).
4. Reich, S. H. & Webber, S. E. Structure-based drug design (SBDD): every structure tells a story. Perspect. Drug Discov. Design 1, 371-390 (1993).
5. Lin, J. H. & Yamazaki, M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin. Pharmacokinet. 42 59-98 (2003).
6. Lin, J. et al. The role of absorption, distribution, metabolism, excretion and toxicity in drug discovery. Curr. Top. Med. Chem. 3, 1125-1154 (2003).
7. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46, 3-26 (2001).
8. Lipinski, C. A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44, 235-249 (2000).
9. Tseng, G.-N. IKr: The hERG channel. J. Mol. Cell. Cardiol. 33, 835-849 (2001).
10. Taglialatela, M. et al. Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity. Clin. Exp. Allergy 29 (Suppl. 3), 182-189 (1999).
11. Redfern, W. S. et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58, 32-45 (2003).
12. Wiseman, E. H. & Lombardino, J. G. in Chronicles of Drug Discovery Ch. 8 (eds Bindra, J. S. & Lednicer, D.) 173-200 (J. Wiley and Sons, Inc., New York, 1982).
13. Sapienza, A. M. & Lombardino, J. G. Recognizing, appreciating, and capturing tacit knowledge of R & D scientists. Drug Dev. Res. 57, 51-57 (2002).
14. Mullen, R. Priming the pipeline. Chem. Eng. News 82 23-42 (2004).
15. Landers, P. Drug industry's big push into technology falls short. The Wall Street Journal A1 (24 February 2004).
16. Big Trouble for Big Pharma. The Economist 14 (16 December 2003).
17. Flynn, J. In two generations, drug research sees a big shift. The Wall Street Journal A1 (11 February 2004).
18. Lombardino, J. G. & Wiseman, E. H. Nonsteroidal Antiinflammatory Drugs - Mechanisms and Clinical Use Ch. 26 (eds Lewis, A. & Furst, D.) 487-506 (Marcel Dekker Inc., New York, 1987).
19. Delay, J., Deniker, P., Green, A. & Mordret, M. Excitor-motor syndromes provoked by ataratics. Presse Medicale (1893-1971), 65 1771-1774 (1957).
20. Granger, B. The discovery of haloperidol. Encephale, 25, 59-66 (1999).
21. Hippius, H. A historical perspective of clozapine. J. Clin. Psychiatry 60 (Supp. 12). 22-23 (1999).
22. Pere, J. J. Clinical psychopharmacology: the example of clozapine (Leponex). Encephale 21 (Spec. No, 3), 9-12 (1999).
23. 2: binding characteristics of some quipazine anaogs. J. Med. Chem. 29, 2375-2380 (1986).
24. Lowe, J. A. et al. 1-naphthylpiperazine derivatives as potential atypical antipsychotic agents. J. Med. Chem. 34, 1860-1866 (1991).
25. 2 ratio hypothesis. Curr. Med. Chem. 1, 50-60 (1994).
26. Howard, H. R. et al. 3-benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents. J. Med. Chem. 39, 143-148 (1996).
27. Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493-502 (2002).
28. Schindler, T. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938-1942 (2000).
29. Bell, I. M. et al. 3-aminopyrrolidinones farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. J. Med. Chem. 45, 2388-2409 (2002).
30. Bell, I. M. et al. Design and biological activity of (S)-4-(5-{[1-(3-Chlorobenzyl)-2-oxopyrrolidin- 3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency. J. Med. Chem. 44, 2933-2949 (2001).