Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore, without necessarily duplicating the topological features of known active compounds (hence remain independent of existing patents). As the 3D searching technology has evolved over the years, it has been effectively used for lead optimization, combinatorial library focusing, as well as virtual high-throughput screening. Clearly established as one of the successful computational tools in rational drug design, we present in this review article a brief history of the evolution of this technology and detailed algorithms of Catalyst, the latest 3D searching software to be released. We also provide brief summary of published successes with this technology, including two recent patent applications.

Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore. As the 3D searching technology has evolved over the years, it has been effectively used for lead optimization, combinatorial library focusing, as well as virtual high-throughput screening. This paper is an update to the original paper published in this journal earlier: Kurogi, Y, and Guner, O. F. "Pharmacophore Modeling and Three-Dimensional Database Searching for Drug Design Using Catalyst," in Current Medicinal Chemistry, 2001, 8(9), 1035-1055.

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We tested the hypothesis that the stable isotope [13 C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the 13 CO 2 produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles were administered a single oral dose of [13 C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled 13 CO 2 and 12 CO 2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13 CO 2 / 12 CO 2 after [ 13 C]pantoprazole relative to 13 CO 2 / 12 CO 2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB 15 to DOB 120 , and area under the DOB versus time curve (AUC 0 -120 and AUC 0 -ϱ ) were significantly different among three genotype groups (CYP2C19*1/ *1, n ϭ 10; CYP2C19*1/*2 or CYP2C19*1/*3, n ϭ 10; and CYP2C19*2/*2, n ϭ 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p Ͻ 0.01); linear regression analysis indicated a gene-dose effect relationship (r 2 ranged between 0.236 and 0.522; all p Ͻ 0.05). These breath test indices were significantly lower in PMs than IMs (p Ͻ 0.05) or EMs (p Ͻ 0.01) of CYP2C19. [13 C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r ϭ Ϫ0.74; p ϭ 0.038). These feasibility data suggest that the [ 13 C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19.

The novel compound NO-1886, 4-[(diethoxyphosphoryl)methyl]-N-(4-bromo-2-cyanophenyl)-ben zamide, is a hypolipidemic agent, which appears to increase lipoprotein lipase activity in rats. Various analogs of NO-1886 were synthesized to study the structure-activity relationship of this hypolipidemic drug. A novel series of quinazolines and 4(3H)-quinazolinones were prepared by cyclization of NO-1886 derivatives. Derivatives bearing a 4-[(diethoxyphosphoryl)-methyl]phenyl] group at the 2-position were found to lower triglyceride and total cholesterol levels. In accord with the decrease in log P*, quinazolines and 4(3H)-quinazolinones showed good absorption and hypolipidemic activity. When the quinazolinone ring system is substituted at positions 6 and 7 with methoxy groups, increased hypolipidemic activity was observed. The highest hypolipidemic activity was observed when the 3-position was substituted by a methyl or benzyl group.