Search

Important resistance patterns in Gram-negative pathogens include active efflux of antibiotics out of the cell via a cellular pump and decreased membrane permeability. A 3-arylpiperidine derivative (1) has been identified by high-throughput assay as a potentiator with an IC50 ∼90 μM. This report details the evaluation of the tether length, aryl substitution and the importance of the fluorine on antibiotic accumulation. Evaluation of various tether lengths demonstrated that the two-carbon tethered analogues are optimal. Removal of the fluorine has a modest effect on antibiotic accumulation and the defluorinated analogue 17 is equally potent to the original lead 1.

This paper describes the discovery of α-trifluoroketoacetamides as potent antibacterial agents against Gram-positive organisms. The initial SAR indicates that the aryl ethyl side chain is essential in maintaining antibacterial activity. The SAR observations have been utilized to design a bioisostere for the α-trifluoroketoacetamide with good activity against Gram-positive organisms.

Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation.

Fatty acid amide hydrolase (FAAH) has attracted significant attention due to its promise as an analgesic target. This has resulted in the discovery of numerous chemical classes as inhibitors of this potential therapeutic target. In this paper we disclose a new series of novel FAAH irreversible azetidine urea inhibitors. In general these compounds illustrate potent activity against the rat FAAH enzyme. Our SAR studies allowed us to optimize this series resulting in the identification of compounds 13 which were potent inhibitors of both human and rat enzyme. This series of compounds illustrated good hydrolase selectivity along with good PK properties.

The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).

The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents has been described in a recent series of papers. This paper describes the discovery of 1-acylindazol-3-ols as a novel bioisostere of an anthranilic acid. The synthesis and structure-activity relationships of the indazol bioisosteres are described herein.

(R)-(−)-2,2-diphenylcyclopentanol intermediate: 2-Amino-3,3-diphenyl-1-cyclopentene-1-carbonitrile reactant: 28.3 mL (0.29 mol) of 4-bromobutyronitrile intermediate: 2,2-Diphenylcyclopentanone product: (R)-(−)-2,2-diphenylcyclopentanol catalyst: 1.5 g (93% recovery) of (S)-α,α-diphenyl-2-pyrrolidinemethanol solvent: hexane reactant: 4-Iodobutyronitrile Keywords: annulation, carbocyclic-[5]; annulation, carbocyclic-[5]; cyclization, condensation; cyclization, condensation; hydrolysis, miscellaneous; reduction, CO CHOH; replacement reactions, halogen by halogen; stereoselective reactions, enantioselective; assay methods, of enantiomeric purity by chiral column HPLC; assay methods, of enantiomeric purity by supercritical field chromatography; assay methods, of enantiomeric purity of sec. amine by chiral column HPLC of p-toluenesulfonamide; tert-butyl methyl ether; dichloromethane (methylene chloride); diphenylacetonitrile, purification; ethyl acetate; hexane; tetrahydrofuran; borane-methyl sulfide complex, flammable; dimethyl sulfide, stench; hydrogen, fire hazard

This paper describes the discovery of α-trifluoroketoacetamides as potent antibacterial agents against Gram-positive organisms. The initial SAR indicates that the aryl ethyl side chain is essential in maintaining antibacterial activity. The SAR observations have been utilized to design a bioisostere for the α-trifluoroketoacetamide with good activity against Gram-positive organisms.

The asymmetric variant of the tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes with chiral vinyl ethers has been extensively explored in recent years.1 To date, the chiral vinyl ethers that have been utilized in the tandem sequence are derived from bornane-2,3-diol, 1, trans-2phenylcyclohexanol, 2, and 2,2-diphenylcyclopentanol, 3, Figure 1. These auxiliaries have served admirably in many aspects of the cycloaddition process, but some limitations still exist, such as the following: (1) length of synthesis, (2) low selectivity in exo mode cycloadditions or (3) unavailability in both enantiomeric series. In the course of a number of total synthesis projects that employ the tandem sequence, we were forced to consider alternatives that addressed some of the limitations noted above.2 In particular, material through-put became an important issue since the critical unmasking of the nitroso acetals to R-hydroxy lactams involves up to a 50%mass loss due to the size of the chiral auxiliaries employed. Thus, it is of critical importance that the auxiliaries be easily prepared and inexpensive. Comins has recently disclosed the use of an easily prepared auxiliary, trans-2-cumylcyclohexanol, 4 (TCC), for the diastereoselective addition of Grignard reagents to alkoxypyridines.3 The preparation of TCC by Comins is considerably more simple than that previously reported by Whitesell, making this auxiliary an interesting alternative for use in the nitroalkene cycloaddition chemistry.4 By analogy with the preparation of the vinyl ethers derived from phenylcyclohexanol, 2, and 2,2-diphenylcyclopentanol, 3, the transetherification of 4 with a vinyl ether was explored.5 TCC is a very sterically crowded auxiliary, since the 1-methyl-1-phenylethane presents a larger steric bulk than the phenyl group in 2-phenylcyclohexanol. Therefore, a higher boiling vinyl ether was required for the trans-etherification. n-Butyl vinyl ether was found to be the vinyl ether of choice as was also the case for 2,2-diphenylcyclopentanol.6 Optimized reaction conditions employed two portions of 0.6 equiv of mercury(II) acetate in a dilute solution of n-butyl vinyl ether as solvent, Scheme 1. The vinyl ether, (-)-5, was isolated in 62% yield along with 33% of recovered alcohol, (-)-4. To evaluate the utility of this new auxiliary in the tandem [4 + 2]/[3 + 2] cycloaddition, the nitroalkene 6 was selected as the model substrate since it had been used previously with all the other chiral vinyl ethers.6 Furthermore, it was imperative to deduce the sense of asymmetric induction exercised by this new auxiliary. We, therefore, needed to establish to which enantiomeric series the final R-hydroxy lactam belonged. Accordingly, slow addition of the nitroalkene 6 to a cold solution of methylaluminum bis(2,6-diphenylphenoxide) (MAPh)7 and vinyl ether (+)-5 afforded the nitroso acetal 7 in 85% yield, Scheme 2. By 1H NMR analysis of HC(6) the product composition was estimated to be a 145/1.8/1.0 (exo/exo/endo) mixture of diastereomeric nitroso acetals. The major diastereomer was assumed to have a trans relationship between HC(4a) and HC(6) on the basis of the documented preference of MAPh to promote exo-mode [4 + 2] cycloadditions.8 The nitroso acetal 7 was then unmasked under the standard hydrogenolysis conditions (Raney nickel/1 atm H2/rt/MeOH). The R-hydroxy lactam, (-)-8, isolated in 76% yield (along with an (1) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (2) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Org. Chem. 1995, 60, 3574. (3) (a) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656. (b) Comins, D. L.; Salvador, J. M. Tetrahedron Lett. 1993, 34, 801. (c) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1994, 35, 7343. (4) Whitesell, J. K.; Lawrence, R. M. Chimia 1986, 40, 318. (5) The vinyl ether of phenmenthol has been prepared earlier in a two-step procedure, by the preparation of the acetylenic ether followed by a partial reduction. Denmark, S. E.; Senanayake, C. B. W.; Ho, G. D. Tetrahedron 1990, 46, 4857. (6) (a) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J. Org. Chem. 1993, 58, 1859. (b) Denmark, S. E.; Schnute, M. E.; Marcin, L. R.; Thorarensen, A. J. Org. Chem. 1995, 60, 3205. (7) (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 4573. (b) Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316. (c) Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 9011. (d) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310. (8) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W. J. Org. Chem. 1993, 58, 1859. Figure 1. Chiral auxiliaries employed in the tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes.

Medicinal Chemistry 7254-209-615, Pharmacia, Kalamazoo, MI 49001-0199, USA Protein Science, Pharmacia, Kalamazoo, MI 49001-0199, USA Computer Aided Drug Discovery Research, Pharmacia, Kalamazoo, MI 49001-0199, USA Discovery Technologies, Pharmacia, Kalamazoo, MI 49001-0199, USA Biology I, Pharmacia, Kalamazoo, MI 49001-0199, USA Structural, Analytical & Medicinal Chemistry Research, Pharmacia, Kalamazoo, MI 49001-0199, USA