The University of California, Santa Barbara
Department of Chemistry & Biochemistry
Presents

THE THIRTY-FIFTH ANNUAL
B. R. BAKER LECTURE

Delivered by

Christopher A. Lipinski
Pfizer Global Research

"Overcoming Efficacy Failure: Drug Repurposing Is The Positive Face Of Drug Discovery Poor Clinical Efficacy Prediction"
Thursday, May 7, 2009 at 3:30 p.m.
Chemistry 1179

Chris Lipinski received his Ph.D. in 1968 in physical organic chemistry from the University of California, Berkeley. He subsequently served as a NIH Postdoctoral fellow at the California Institute of Technology with Bob Ireland. At the Pfizer Global Research and Development Groton Laboratories from 1970 to 1990, Dr. Lipinski oversaw the development of numerous drug candidates for the treatment of gastrointestinal and diabetic diseases. While working at Pfizer, he became very interested in the design of bioisosteres for improving efficacy as well as in the physical chemical properties of compounds that ultimately relate to their adsorption, distribution, metabolism, excretion and toxicity (ADMET). He subsequently published a landmark paper, "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings" Advanced Drug Delivery Reviews, 1997, 23, 3-25, which has been cited over sixteen hundred times and which averages over one hundred and twenty citations per year. In this publication, Dr. Lipinski has championed a very pragmatic approach to the problem of oral activity improvement for drug candidates, that has become known as "The Rule of Five " based on the observation that most medication drugs are relatively small and lipophilic molecules. This publication has significantly influenced the way that the pharmaceutical industry approaches the development of orally active drugs. Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria: not more than 5 hydrogen bond donors, not more than 10 hydrogen bond acceptors, a molecular weight of under 500 daltons, and an octanol-water partition coefficient log P of less than 5. Note that all numbers are multiples of five, hence the origin of the rule's name. The rule filters out molecules that are likely to have poor intestinal permeability or poor aqueous solubility, and hence poor oral absorption. Today drug discovery programs worldwide use the Rule in their go/no-go decision-making processes.

Dr. Lipinski is a member of the TB Alliance Scientific Advisory Committee. He is recipient of an honorary law degree from the University of Dundee , a winner of Society for Biomolecular Sciences (SBS) 2006 Achievement Award for Innovation in HTS , winner of the 2005 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances from the American Chemical Society, 2004 winner of the Medicinal Chemistry Award from the American Chemical Society Division of Medicinal Chemistry. Dr. Lipinski has been an adjunct faculty member at Connecticut College in New London CT since 1984, and has over 210 publications and invited presentations and 17 issued US patents. He is presently a consultant for Melior Discovery, Inc

Professor B.R. Baker was a Professor of Chemistry at UCSB from 1966 until his death in 1971. Baker's graduate work on the structural elucidation and synthesis of Cannabis constituents marked the beginning of a prolific career in the chemistry of natural products. He undertook many diverse projects of medicinal interest including the synthesis of antihemorrhagic vitamin K analogues, biotin derivatives, compounds with hormone activity, sulfones with activity against tuberculosis, and alkaloids. He published two books and more than 370 papers that included a series of papers on the structure and synthesis of the antimalarial alkaloid from Hydrangea that filled an entire issue of the Journal of Organic Chemistry in 1952. He determined the structure of the first known nucleoside antibiotic, puromycin, and synthesized it in 1955. This achievement came long before the discovery of the structure of transfer ribonucleic acid (tRNA). Puromycin was later shown to mimic the structure of tRNA and became and an important tool of research in molecular biology. Puromycin was too toxic for cancer chemotherapy, but it aroused Bill's interest in this field. Few of the myriad of compounds that he had so meticulously synthesized showed any antitumor activity in vivo, so he sought a more rational approach to cancer chemotherapy. Perhaps his greatest contribution to medicinal chemistry was the concept of active-site-directed irreversible enzyme inhibition of substrate-identical enzymes. A monograph summarizing this approach to drug design promptly became on of the classic works in the field.

Past lecturers: