Integration of Pharmaceutical Discovery and Development: by Ronald T. Borchardt, Roger M. Freidinger, Tomi K. Sawyer,
By Ronald T. Borchardt, Roger M. Freidinger, Tomi K. Sawyer, Philip L. Smith
This quantity offers case histories illustrating the categories of interdisciplinary interactions essential to layout drug applicants with optimum pharmacological, pharmaceutical, biopharmaceutical, and metabolic/pharmacokinetic homes. Key good points comprise an incisive dialogue of HIV protease inhibitors and 287 illustrations.
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2:814–817. Saul H. Rosenberg and Hollis D. Kleinert 26 Goa, K. , and Wagstaff, A. , 1996, Losartan potassium: A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension, Drugs 51:820–845. Greenlee, W. , 1990, Renin inhibitors, Med. Res. Rev. 10:173–236. Israili, Z. , and Hall, W. , 1992, Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy, Ann. Intern. Med. 117:234–242. James, M. N. , Rich, D. , and Hofmann, T, 1982, Conformational flexibility in the active site of aspartyl proteinases revealed by a pepstatin fragment binding to penicillopepsin, Proc.
C. Nicolaou, and I embarked on a research program to replace the secondary amide bonds by alternate scaffolds. The program with Smith led to the design and synthesis of HIV-1 protease inhibitors in which an NH-displaced pyrrolinone scaffold replaced the amide backbone. Pleasingly, assay results obtained at Merck suggested that these pyrrolinone-based enzyme inhibitors displayed better transport into the lipid bilayer of lymphocytes than did their peptide counterparts. We proposed an explanation for the improved transport properties of the pyrrolinones vis-à-vis their peptide counterparts based on the observation by W.
5. Summary and Future Directions . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . 582 583 583 585 590 591 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Chapter 1 Introduction Ralph Hirschmann It is a pleasure to write an introduction to this timely book. As the reader is well aware, drug discovery has changed dramatically during the second half of this century. Let me cite a few examples.