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The world's countries have committed to assure by 2030 reliable mobility to all, even in the largest cities. Review of experience of three fastest-growing cities in South Asian countries underlines reforms that will need to be applied very widely: more private-vehicle restrictions in dense zones, and reservation of some road-lanes for bus use; rapid expansion of metro/bus systems, with service franchises subject to periodic open competition; integration of land-use and transport planning, at street and city level; active collaboration of the planners with developers and builders; activation of competitive building of affordable housing; radical improvement of land market functioning; modernization of traditional building-height restrictions to encourage greater variation, against appropriate payment to the state; increased provision and maintenance of pedestrian and bicycle infrastructure and safety; and consideration of tolling use of private vehicles for journeys that would otherwise be undertaken by mass transit.

Embryotoxicity studies on irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS-91524-15-1), a new fluoroquinolone antibacterial agent, were performed in rats and rabbits. Oral administration of irloxacin during the fetal period of organogenesis to pregnant rats and rabbits at dose levels of up to 1000 and 350 mg/ kg/d, respectively, elicited no evidence of teratogenicity. During the first days of treatment, transient stasis in body weight increase was observed in rat dams receiving doses of 350 or 1000 mg/ kg/d, and reduced food consumption was obeserved in those receiving 1000 mg/kg/ d. Necropsy on day 20 of gestation showed dosage related increase in liver and kidney weights in all rat treated groups. Rabbit dams receiving 350 mg/ kg/d showed during the first days of treatment decrease in body weight, and decreased food consumption and faecal output. Also, four females receiving 350 mg/ kg/d aborted between days 18 and 20 of gestation. Rat fetuses in the 350 and 1000 mg/kg/d showed decreased body weight, and a decrease in placental weights was observed in the 1000 mg/kg/ d group. No retardations or malformations were observed in rat or rabbit fetuses at any tested dose level. For maternal and embryo-fetal effects 100 and 150 mg/kg/d can be considered as the no-effect-level (NOEL) for rats and rabbits, respectively.

The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.

A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.

A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC95=50 nM). Compound 4a also has improved PK properties relative to 1.

Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.

Herein we report the preparation of a combinatorial library of compounds with potent CCR5 binding affinity. The library design was aided by SAR generated in a traditional medicinal chemistry effort. Compounds with novel combinations of subunits were discovered that have high binding affinity for the CCR5 receptor. A potent CCR5 antagonist from the library, compound 11 was found to have moderate anti-HIV-1 activity.

Background: Granzyme B, one of the most abundant granzymes in cytotoxic T-lymphocyte (CTL) granules, and members of the caspase (cysteine aspartyl proteinases) family have a unique cleavage specificity for aspartic acid in P1 and play critical roles in the biochemical events that culminate in cell death. Results: We have determined the three-dimensional structure of the complex of the human granzyme B with a potent tetrapeptide aldehyde inhibitor. The Asp-specific S1 subsite of human granzyme B is significantly larger and less charged than the corresponding Asp-specific site in the apoptosis-promoting caspases, and also larger than the corresponding subsite in rat granzyme B. Conclusions: The above differences account for the variation in substrate specificity among granzyme B, other serine proteases and the caspases, and enable the design of specific inhibitors that can probe the physiological functions of these proteins and the disease states with which they are associated.

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.

A method for the solid phase synthesis of aryl amines is reported. The method involves a palladium mediated coupling reaction between aryl bromides and amines. The products are isolated in high purity and good yields. This method should prove to be a useful tool for constructing combinatorial libraries containing the aryl amine moiety.

The preparation of novel titanium complexes bearing o-phosphinophenol ligands is reported. The feature of this ligand system is that its electronic and steric properties can be independently tuned. The complexes were found to be fluxional by 1H NMR analysis at low temperature. An X-ray structural analysis showed that in the solid state the molecule is chiral at the metal center. These complexes were shown to be effective catalysts for olefin hydrogenation and imine hydrosilylation.

A 55-year-old woman came to the emergency department because of an episode of post-prandial upper abdominal pain radiating to her back and associated with nausea and vomiting. The pain had been recurring intermittently for approximately six months. While in the emergency department, she had another episode of pain and felt lightheaded. Her pulse rate at that point was between 30 and 40 beats per minute, and an electrocardiogram was recorded (Figure).

The asymmetric hydrogenation of cyclic ketimines with a chiral titanocene catalyst affords amines with excellent enantioselectivity under a variety of conditions. The reaction is general for cyclic imines of ring size 5-7 and exhibits a high degree of functional group compatibility

A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.

Cervarix™ is a prophylactic human papillomavirus (HPV)-16/18 vaccine for the prevention of cervical cancer. It contains GSK Biologicals' proprietary Adjuvant System AS04. The objective of this study was to investigate the effects of Cervarix™ and of AS04 on female fertility and pre- and post-natal development in Sprague Dawley rats. Female rats were injected with vaccine, AS04, or saline 30 days before mating and on Gestation Days 6, 8, 11 and 15. Each dose of vaccine was one-fifth the human dose volume. Treatment of rats with vaccine or AS04 was not associated with any systemic toxicity and had no impact on female fertility. There were no adverse effects on pre- or post-natal development of litters from treated rats, as judged by fetal evaluation at Gestation Day 20, and growth and survival of pups to postnatal Day 25. These results support the use of the vaccine in the targeted human population.

The need to routinely perform a two-generation study to assess reproductive performance is under debate. This review has analysed the results from 22 consecutive Two-Generation Reproduction Toxicity Studies performed within our laboratories, to determine the value of mating each generation in the detection of treatment-related effects on reproductive performance. The chemicals included 13 agrochemicals, 5 industrial chemicals and 4 food additives. Four chemicals (all from the agrochemical group) were found to have clear treatment-related effects and in three studies effects were confined to the second (F1) generation. For the three studies with second (F1) generation effects, we applied the triggers, proposed by the Agricultural Chemical Safety Assessment (ASCA) Technical Committee of HESI, for extension of the one-generation study and found that mating of the second (F1) generation would have been triggered in these studies by effects on the F1 offspring growth and sexual maturation. No effects were seen in the original parental (F0) generation which would have activated the change from a one- to a two-generation study.

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.

The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.

The synthesis of a series of novel dihdyropyridine diacid glycogen phosphorylase inhibitors is presented. SAR and functional assay data are discussed, along with the effect of a single inhibitor on blood glucose in a diabetic animal model.

Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.

A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.

The asymmetric hydrogenation of cyclic ketimines with a chiral titanocene catalyst affords amines with excellent enantioselectivity under a variety of conditions. The reaction is general for cyclic imines of ring size 5-7 and exhibits a high degree of functional group compatibility

Methodology was developed to afford rapid characterization of multicomponent mixtures of small organic molecules prepared by split-and-mix combinatorial synthesis. This methodology involved the use of liquid chromatography mass spectrometry (LC/MS) combined with correlation analysis of measured versus predicted electrospray ionization mass spectra. Low-resolution mass spectra of complex mixtures revealed predictable patterns that confirm library products, assisted in identifying chemical synthesis errors, and assessed overall library integrity. In general, equal signal intensities were observed for most combinatorial mixture components, indicating that differences in electrospray ionization efficiency was not a major limitation to this approach. High-throughput data processing programs and informatics tools were used to speed data analysis and to simplify the presentation of the library characterization results. This approach has been used to characterize combinatorial libraries that were synthesized for a variety of drug-discovery programs. Examples are shown for library formats of 1, 40, 66, 280, and 400 component(s)/well. The applicability of this approach to large combinatorial mixtures should allow direct characterization of massive combinatorial libraries.

(R,R,R) [143063-72-3] C40H36O2Ti (MW 596.64) InChI = 1S/C20H14O2.C20H24.Ti/c21-17-11-9-13-5-1-3-7-15(13)19(17)20-16-8-4-2-6-14(16)10-12-18(20)22;1-3-7-19-15(5-1)9-11-17(19)13-14-18-12-10-16-6-2-4-8-20(16)18;/h1-12,21-22H;9-12H,1-8,13-14H2;/q;;+2/p-2 InChIKey = ZVPRKHQZEULVLC-UHFFFAOYSA-L (S,S,S) [83417-93-0] InChI = 1S/C20H14O2.C20H24.Ti/c21-17-11-9-13-5-1-3-7-15(13)19(17)20-16-8-4-2-6-14(16)10-12-18(20)22;1-3-7-19-15(5-1)9-11-17(19)13-14-18-12-10-16-6-2-4-8-20(16)18;/h1-12,21-22H;9-12H,1-8,13-14H2;/q;;+2/p-2 InChIKey = ZVPRKHQZEULVLC-UHFFFAOYSA-L (precursor to a catalyst for the asymmetric reduction of unsaturated organic molecules1) Physical Data: mp 274.5–277 °C (dec); [α]578, −3700° (c = 0.45 mg cm−3 in CHCl3). Solubility: sol THF, benzene, toluene; slightly sol ether; very slightly sol hexane. Preparative Methods: originally prepared and characterized by Brintzinger et al. from the corresponding dichloride derivative and (R)-1,1′-Bi-2,2′-naphthol.2 The dichloride is synthesized by reacting the dilithium salt of 1,2-bis(3-indenyl)ethane with Titanium(IV) Chloride followed by hydrogenation over Platinum(IV) Oxide.2 Since the original report, two improved procedures for its preparation have appeared.3, 1b Handling, Storage, and Precautions: the complex is air and moisture stable and can be stored indefinitely.

Two phthalate esters, di-(C7-C9 alkyl) phthalate (D79P) and di-(C9-C11 alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.

The synthesis and X-ray structure determination of the novel complex, Cp2Ti(Ph2SiH2)(PMe3), 4 is reported. The spectroscopic and structural data indicate that 4 is best described as being a hybrid between a titanium(IV) (silyl)hydride complex and a titanium(II) silane complex. Complex 4 reacts reversibly with N2 to form the bridging dinitrogen complex 5 and, in the presence of norbornene, 4 catalytically dimerizes Ph2SiH2 in quantitative yield. Silane complex, Titanium

I count it a great honor to be invited to participate in a world conference on the important subject of transportation research. Particularly so when the conference is sponsored by a country which has played such an innovative role as the Netherlands have in the main job of our era, the search for paths of reconciliation and constructive cooperation between rich North and poor South, between all Worlds, from first to fourth. And, too, particularly so when the conference takes place in Rotterdam, greatest hub of the global transport system which is the physical expression of growing interdependence among countries. I would like to pay special tribute to the foresight and several years’ hard work of Dr. Noortman and the Netherlands Institute of Transport in taking the initiative to organize the conference.