MEDICINAL AND COMBINATORIAL CHEMISTRY
Noting that some enzyme inhibitors form aggregates in solution, Brian K. Shoichet of Northwestern University, Evanston, Ill., and coworkers found this year that the inhibitory potency of such enzymes correlates with aggregate formation--and not with the binding affinity of individual inhibitor molecules to targets, as had generally been believed [J. Med. Chem., 45, 1712 (2002); C&EN, April 1, page 11].
James J. Crute and coworkers at Boehringer Ingelheim R&D and Gerald Kleymann and coworkers at Bayer AG, Wuppertal, Germany, independently discovered potential alternatives to acyclovir, valacyclovir, and famciclovir, the current drugs used to treat herpes simplex infections [Nat. Med., 8, 386 and 392 (2002); C&EN, April 8, page 11]. The new agents inhibit a virally encoded helicase-primase enzyme--a novel target for drug discovery.
The manic-depression treatments lithium, carbamazepine, and valproic acid were believed to act in different ways. But Anne W. Mudge, Adrian J. Harwood, and coworkers at University College London found that all three actually share the same mechanism of action--depletion of inositol, a precursor to key signaling molecules [Nature, 417, 292 (2002); C&EN, May 20, page 37].
Mark B. Pepys of Royal Free & University College Medical School, London, and coworkers developed a compound that clears the amyloid fibril-protecting protein SAP from circulation, dissociates SAP from amyloid fibrils, and may promote regression of amyloid deposits in human amyloid diseases [Nature, 417, 254 (2002); C&EN, May 20, page 37]. "It is the first demonstration that a small-molecule drug can be used to effectively produce almost complete depletion of a circulating plasma protein in man," Pepys says. Clinical studies are under way.
Daniel F. Veber and coworkers at GlaxoSmithKline, King of Prussia, Pa., discovered that low molecular flexibility (low number of freely rotatable bonds) correlates with high oral bioavailability [J. Med. Chem., 45, 2615 (2002); C&EN, June 10, page 9]. The findings suggested that new drugs could be found even among traditionally less promising high-molecular-weight compounds, provided their rigidity is maximized.
Daniel L. Simmons and coworkers at Brigham Young University, Provo, Utah, discovered COX-3, a new variant of the enzyme cyclooxygenase, and found that it may be the target of the popular analgesic acetaminophen [Proc. Natl. Acad. Sci. USA, 99, 13926 (2002); C&EN, Sept. 23, page 16].
A Wilmington, Del.-based Bristol-Myers Squibb group led by James J.-W. Duan used rational design to develop a new class of substituted -lactams that inhibit the metalloprotease responsible for producing tumor necrosis factor--which is present in abnormally high amounts in rheumatoid arthritis patients [J. Med. Chem., 45, 4954 (2002); C&EN, Nov. 18, page 60]. A structurally related compound is in clinical trials.
Among combinatorial chemistry developments this year, Ming-Shang Kuo and coworkers at Pharmacia developed a system in which chromatography and four analyzers are used to evaluate, in a single experiment, the identity, purity, and concentration of compounds made by parallel synthesis [J. Comb. Chem., 4, 138 (2002); C&EN, March 18, page 11].
By using a synthetase enzyme to convert peptides into macrocycles, Christopher T. Walsh of Harvard Medical School and coworkers created a combinatorial library of potential antibiotics, some of which show promising activity against drug-resistant microbes [Nature, 418, 658 (2002); C&EN, Aug. 12, page 10].
The selective amplification of two different "hosts" (receptors) for two different "guests" in a dynamic combinatorial chemistry (DCC) library was achieved by Sijbren Otto and coworkers at Cambridge University, in England [Science, 297, 590 (2002); C&EN, Sept. 2, page 31]. In the study, small variations in host-guest binding affinity led to significant and useful amplification differences.
||AMPLIFICATION In a dynamic combinatorial chemistry study by Otto and coworkers, addition of a guest molecule (template) resulted in amplification of one of the equilibrating hosts (receptors)--the host that bound most strongly to the guest.