CHEMICAL & ENGINEERING
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JUNE 10, 2002 •• ^DITED BY JANICE LONG & STEPHEN W . irRZAs^Aj
DRUG
DEVELOPMI
NEWWAY"f6 ASSESS DRUG CANDIDATES Team finds that rigiid compounds tend to be more orally bi oavailable Jk
NOVEL STRUCTURAL PA-
m\ rameter can predict the # m oral bioavailability of a drug—that is, the degree to which it becomes systemically available when taken by mouth. A research team finds that compounds with good oral bioavailability tend to have reduced molecular flexibility, as measured by the number of freely rotatable bonds. The study was carried out by researchers Daniel F. Veber, Stephen R.Johnson, Hung-Yiian Cheng, Brian R. Smith, Keith W Ward, and Kenneth D. Kopple at GlaxoSmithKline, King of Prussia, Pa. \J. Med. Chem., 45, 2615 (2002)}. The paper highlights "the importance of rotatable bonds in determining oral bioavailability, independent of molecular weight," Veber says. Low molecular weight has generally been considered a prerequisite for "druglike" properties. "Our analysis opens the possibility that new drugs can be found more easily in the high-molecular-weight range, provided the number of rotatable bonds is minimized." For the past few years, the "rule of five" developed by senior research fellow Christopher A. Lipinski (now retired) and colleagues at Pfizer in Groton, Conn., has been the standard approach for predicting oral bioavailability from structure data. "The number five or a mulHTTP://PUBS.ACS.ORG/CEN
that are orally bioavailable." In pharmaceutical research, "we used to improve potency all we could, and very often we ended up with compounds t h a t were very insoluble and not available orally," Hirschmann says. "But in the past 15 years, the industry has learned that you had better worry about oral bioavailability early on in the game. The more rules you have to guide you in that endeavor, the better off you are." As soon as the paper by Veber and coworkers "popped up on theJournalofMedicinal Chemistry site, people here in Groton were
tiple occurs in all of the cutoff parameters," Lipinski explains, "but there are only four rules — involving molecular weight, number of hydrogen bond donors and acceptors, and lipophilicity." T h e new rotatablebond rule complements the rule of five. Veber and z coworkers discovered X 1the parameter by studyl/l o ing 1,100 c o m p o u n d s x < in GlaxoSmithKline's archive. About 65% of fairly rigid compounds in the collection (those with seven or fewer rotatable bonds) exhibited good-toexcellent oral bioavailability, independent of molecular weight. In contrast, more than 75% of floppy compounds (those with more than 10 rotatable bonds) had poor oral bioavailability. C o m pounds of intermediate INTF IGUING FINDING Pharmaceut ical researchers (from rigidity fell somewhere in lef t) VVard, Smith, Veber, Kopple, Johns on, and Cheng between. The scientists discos/ered a new way to predict oral bi Davailability. caution that data on oral bioavailability in rats were used circulating it," Lipinski says. "It's in the study, so the results may an intriguing finding, but it's alnot correspond exactly to human so puzzling, because there's realoral bioavailabilities. ly no clear explanation of where the parameter is coming from. "It's very important work, and So when people look at this pait's original," comments profesper, they may scratch their heads, sor of bioorganic chemistry but it will prompt them—in their Ralph F. Hirschmann of the Uniown data sets—to look and see if versity of Pennsylvania. "It's a there's any relationship between valuable addition to the armarotatable bonds and oral bioavailmentarium of how to end up with ability"—STU BORMAN candidates for safety assessment 3
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