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It is frequently mentioned that QSARs have not generally lived up to expectations, especially in cases where high predictability is expected yet failed to deliver satisfactory results. Even though outliers can provide an increased opportunity in drug discovery research, outliers in SAR and QSAR can contort predictions and affect the accuracy if proper attention is not given. The percentages of outliers in QSARs have not changed appreciably over the last decade. In our previous studies, we suggested two possible sources of outliers in SAR and QSAR. In this paper, we suggest an additional possible source of outliers in QSAR. We presented several literature examples that show one or more water molecules that play a critical role in protein-ligand binding interactions as observed in their crystal structures. These examples illustrate that failing to account for the effects of water molecules in protein-ligand interactions could mislead interpretation and possibly yield outliers in SAR and QSAR. Examples include cases where QSAR, considering the role of water molecules in protein-ligand crystal structures, provided deeper insight into the understanding and interpretation of the developed QSAR.

A logic to cell-cell recognition There has been exciting progress in the field of cancer immunotherapy, which harnesses a patient's own immune system to kill cancer cells. However, achieving precise recognition of cancer cells remains challenging. Cells engineered with synthetic Notch (synNotch) receptors bind to specific antigens, and binding induces the expression of defined genes. Williams et al. used synNotch modules as transcriptional connectors that daisy-chain together multiple receptors. They engineered T cells that can recognize up to three target antigens expressed on or inside cancer cells and integrated these inputs to achieve NOT, AND, and OR logic. The engineered cells achieved precise recognition of targeted cancer cells. Science , this issue p. 1099

Cell adhesion molecules are ubiquitous in multicellular organisms, specifying precise cell–cell interactions in processes as diverse as tissue development, immune cell trafficking and the wiring of the nervous system1–4. Here we show that a wide array of synthetic cell adhesion molecules can be generated by combining orthogonal extracellular interactions with intracellular domains from native adhesion molecules, such as cadherins and integrins. The resulting molecules yield customized cell–cell interactions with adhesion properties that are similar to native interactions. The identity of the intracellular domain of the synthetic cell adhesion molecules specifies interface morphology and mechanics, whereas diverse homotypic or heterotypic extracellular interaction domains independently specify the connectivity between cells. This toolkit of orthogonal adhesion molecules enables the rationally programmed assembly of multicellular architectures, as well as systematic remodelling of native tissues. The modularity of synthetic cell adhesion molecules provides fundamental insights into how distinct classes of cell–cell interfaces may have evolved. Overall, these tools offer powerful abilities for cell and tissue engineering and for systematically studying multicellular organization.

Spinal cord injury (SCI) is associated with marked bone loss and an increased risk of fracture. We randomized 61 individuals with chronic SCI and low bone mass to receive either teriparatide 20 μg/d plus sham vibration 10 min/d (n = 20), placebo plus vibration 10 min/d (n = 20), or teriparatide 20 μg/d plus vibration 10 min/d (n = 21). Patients were evaluated for 12 months; those who completed were given the opportunity to participate in an open-label extension where all participants (n = 25) received teriparatide 20 μg/d for an additional 12 months and had the optional use of vibration (10 min/d). At the end of the initial 12 months, both groups treated with teriparatide demonstrated a significant increase in areal bone mineral density (aBMD) at the spine (4.8% to 5.5%). The increase in spine aBMD was consistent with a marked response in serum markers of bone metabolism (ie, CTX, P1NP, BSAP), but no treatment effect was observed at the hip. A small but significant increase (2.2% to 4.2%) in computed tomography measurements of cortical bone at the knee was observed in all groups after 12 months; however, the magnitude of response was not different amongst treatment groups and improvements to finite element-predicted bone strength were not observed. Teriparatide treatment after the 12-month extension resulted in further increases to spine aBMD (total increase from baseline 7.1% to 14.4%), which was greater in patients initially randomized to teriparatide. Those initially randomized to teriparatide also demonstrated 4.4% to 6.7% improvements in hip aBMD after the 12-month extension, while all groups displayed increases in cortical bone measurements at the knee. To summarize, teriparatide exhibited skeletal activity in individuals with chronic SCI that was not augmented by vibration stimulation. Without additional confirmatory data, the location-specific responses to teriparatide would not be expected to provide clinical benefit in this population. © 2018 American Society for Bone and Mineral Research.

Spinal cord injury (SCI) is associated with marked bone loss and an increased risk of fracture. We randomized 61 individuals with chronic SCI and low bone mass to receive either teriparatide 20 μg/d plus sham vibration 10 min/d (n = 20), placebo plus vibration 10 min/d (n = 20), or teriparatide 20 μg/d plus vibration 10 min/d (n = 21). Patients were evaluated for 12 months; those who completed were given the opportunity to participate in an open-label extension where all participants (n = 25) received teriparatide 20 μg/d for an additional 12 months and had the optional use of vibration (10 min/d). At the end of the initial 12 months, both groups treated with teriparatide demonstrated a significant increase in areal bone mineral density (aBMD) at the spine (4.8% to 5.5%). The increase in spine aBMD was consistent with a marked response in serum markers of bone metabolism (ie, CTX, P1NP, BSAP), but no treatment effect was observed at the hip. A small but significant increase (2.2% to 4.2%) in computed tomography measurements of cortical bone at the knee was observed in all groups after 12 months; however, the magnitude of response was not different amongst treatment groups and improvements to finite element-predicted bone strength were not observed. Teriparatide treatment after the 12-month extension resulted in further increases to spine aBMD (total increase from baseline 7.1% to 14.4%), which was greater in patients initially randomized to teriparatide. Those initially randomized to teriparatide also demonstrated 4.4% to 6.7% improvements in hip aBMD after the 12-month extension, while all groups displayed increases in cortical bone measurements at the knee. To summarize, teriparatide exhibited skeletal activity in individuals with chronic SCI that was not augmented by vibration stimulation. Without additional confirmatory data, the location-specific responses to teriparatide would not be expected to provide clinical benefit in this population. © 2018 American Society for Bone and Mineral Research.

We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.

Structure-activity relationship (SAR) and/or quantitative structure-activity relationship (QSAR) studies play an important role in a lead optimization of drug discovery research. When there is a lack of ligand-bound protein structural information, one of the assumptions in SAR and QSAR studies is that similar analogs bind to the same binding site in a similar binding mode. In such studies, outliers have often been observed, especially in QSAR. However, most of these studies have focused their attention on the development of QSAR and left outliers unattended. We searched ligand-bound X-ray crystal structures from the protein structure database to find evidences that could indicate a possible source of outliers in SAR or QSAR. Our results showed the possibility of conformational changes in a flexible binding site as one possible source of outliers.

Continuous wave (CW) microwave discharges operated at atmospheric pressure in argon gas were applied to surface modification of metal surfaces for improvement of adhesion with paint coating. The surface treatment was carried out by making use of the microwave discharges excited in a rectangular waveguide. The charged particles in the discharge plasma with high kinetic energy bombard the substrate, cleaning and etching its surface in rough morphology and polluted with organic compounds. The samples before and after plasma treatment were characterized by a scanning electron microscopy (SEM) and a contact angle analyzer.

Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure–activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC50 values in the single-digit micromolar to submicromolar range).

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.

Substituted 3-amino-2-hydroxyamides and related hydroxyamides and acylhydrazines were identified as inhibitors of human methionine aminopeptidase-2 (MetAP2). Examination of substituents through parallel synthesis and iterative structure-based design allowed the identification of potent inhibitors with good selectivity against MetAP1. Diacylhydrazine 3t (A-357300) was identified as an analogue displaying inhibition of methionine processing and cellular proliferation in human microvascular endothelial cells (HMVEC).

3-D-Quantitative structure–activity relationships of N -(3-acyloxy-2-benzylpropyl)- N ′-dihydroxytetrahydro-benzazepine and tetrahydroisoquinoline and N -(3-acyloxy-2-benzylpropyl)- N ′-(4-hydroxy-3-methoxybenzyl) thiourea analogues as potent vanilloid receptor ligands were investigated using the CoMFA and the COMSIA methods. The best CoMFA model obtained in this study from 29 substituted thiourea analogues is a two-component model with the following statistics. R 2 (cv) =0.407 and RMSE (cv) =0.532 for the cross-validation, and R 2 =0.705 and RMSE=0.375 for the fitted. The best COMSIA model obtained from the same 29 compounds is a two-component model with the following statistics: R 2 (cv) =0.336 and RMSE (cv) =0.563 for the cross-validation, and R 2 =0.693 and RMSE=0.382 for the fitted.

A series of indole containing oxazolines has been discovered as a result of structural modifications of the lead compound A-105972. The compounds exert their anticancer activity through inhibition of tubulin polymerization by binding at the colchicine site. A-289099 was identified as an orally active antimitotic agent active against various cancer cell lines including those that express the MDR phenotype. The anticancer activity, pharmacokinetics, and an efficient and enantioselective synthesis of A-289099 are described.

Thermodynamic quantitative structure–activity relationships (QSAR) for chymotrypsin–ligand binding is developed, and the results are compared for the effects of organic solvent on the substrate specificity of the enzymes to those in aqueous phosphate buffer. This is the first of such analysis utilizing thermodynamic QSAR. A possible explanation for the difference describing the effects of organic solvent for the binding of substituted phenyl esters of N -benzoyl l -alanine analogues [PhCONHCH(Me)COOC 6 H 4 -p-X, I ] observed in both the classical and the thermodynamic QSAR is presented.

3D-Quantitative structure-activity relationships of 2,4,5- and 2,3,4,5-substituted imidazoles as a novel class of potent and nontoxic modulators of Pgp mediated MDR were investigated using CoMFA and COMSIA approaches. The best CoMFA model obtained from 46 imidazole analogues is a two-component model with the following statistics. R(2)(cv)=0.643, RMSE(cv)=0.360 for the cross-validation, and R(2)=0.767, RMSE=0.290 for the fitted. The best COMSIA model obtained is also a two-component model with the following statistics. R(2)(cv)=0.619, RMSE(cv)=0.372 for the cross-validation, and R(2)=0.765, RMSE=0.292 for the fitted.

A protein contains a large amount of water molecules, and the nature of the interactions of the water molecules with a protein play an important role in the thermodynamics of the ligand binding process. In this paper, thermodynamic aspects of drug-receptor interactions, enthalpy-entropy compensation or reinforcement, hydrophobicity, and biological 2D- and 3D-QSAR are discussed. Comparisons of the thermodynamic QSAR of phenyl esters of N-benzoyl L-alanine in phosphate buffer and pentanol provide useful insight for the ligand-enzyme interactions.

Several 1,2,3,4-tetrahydro- and 7-N-hydroxycarbamate derivatives of the natural product rapamycin were prepared and assayed for their immunosuppressive and antifungal profiles. Substitutions at the 7-position indicate the possibility of a differentiated immunosuppressive to antifungal profile, whereas 40-position variants of the tetrahydro-analogues did not show similar differentiated activity.

Neuronal nicotinic acetylcholine receptors represent a new and potentially useful target for the development of novel non-opioid, non-NSAID (nonsteroidal antiinflammatory drug) analgesic agents. A variety of nicotinic acetylcholine receptor agonists such as nicotine, epibatidine and the azetidinyl ether, (R)-5-(2-azetidinylmethoxy-2-chloropyridine (ABT-594) possesses significant efficacy in preclinical models of pain. A preponderance of evidence suggests that nicotinic acetylcholine receptor agonists produce their analgesic effects predominantly via activation of descending inhibitory pain pathways originating in the key brainstem regions of the nucleus raphe magnus, dorsal raphe, and locus coeruleus, and that alpha4-containing nicotinic acetylcholine receptor subunits mediate these effects. Although these studies may provide a pharmacological target for the development of nicotinic acetylcholine receptor analgesics, the rational design of selective ligands based on the protein structure of the binding site is hampered by insufficient structural information. Using an approach based upon homology to known high-affinity ligands for the alpha4beta2 binding site, a four-point model is proposed which defines distance and directionality parameters common to this set of nicotinic acetylcholine receptor ligands.

Quantitative structure-activity relationships of 34 pyrrolidine-modified nicotine agonists are investigated for their binding affinity toward neuronal nicotinic acetylcholine receptor. The results indicate that a large substituent at the R1, R2, and R3 position is detrimental to the binding affinity. Likewise, a large substituent at the R2 alpha or R3 alpha position as well as a hydrogen bond accepting substituent at the R2 beta position are not beneficial to the binding.

Quantitative structure-activity relationships (QSAR) of sixty 1-phenyl-[2H]-tetrahydrotriazin-3-one (I) analogues are examined for the inhibitory potency of 5-lipoxygenase in a broken cell, IC50. Potency is increased by lipophilic substituents at the 3′-, 5′-, and 5-positions. Potency is also increased with 3′- and 5′-substituents that withdraw electrons and decreased with 3′,-substituents on the pyridyl ring that donate electrons. On the other hand, the potency decreases as the size of 2′-substituents increases. Thiourea analogues are about 1.6 times more potent than the corresponding carbonyl analogues.

Quantitative structure-activity relationships (QSAR) of 72 1-phenyttetrahydropyridazin-3(2H)-one (I) analogues are examined for the inhibitory potency (IC S0 ) of 5-lipoxygenase in a broken cell. The potency is increased by lipophilic substituents at the 3’- and 4’-positions. Substituents with positive 7 value at the 4’-position also increase the potency, while substituents at the 3’-position with a positive C R value decrease it. The potency also decreases as the size of the 2’- and/or 4’-substituents increases. Thioketone analogues are about 5 times more potent than the corresponding carbonyl analogues.

Quantitative structure-activity relationships of 44 substituted aminotetralin analogues with regard to dopamine (DA) uptake inhibitory potency are examined in this study. Lipophilic substituents at R3 and hydrophilic substituents at R6 and/or R9 positions, as well as the overall lipophilicity of the molecule contribute toward increasing the inhibitory potency. Unlike with norepinephrine uptake inhibition, little effects are seen from the nitrogen substituent. Among the ring substituents examined, an hydroxy group at the R6 position increases the DA uptake inhibitory potency, whereas a methoxy group at the R7 position decreases it. A comparative quantitative structure-activity relationship study shows that a bromine at the R6 position and/or hydrogen at the R9 position make the compound a better norepinephrine uptake inhibitor than a DA uptake inhibitor, whereas hydrogen at the R6 and/or a substituent larger than a propyl group at the R2 position make the compound a more potent DA uptake inhibitor.

The applicability of the comparative molecular field analysis (CoMFA) approach to describe the nonlinear dependence of biological activity on lipophilicity in 3D quantitative structure-activity relationships (QSAR) has been demonstrated. The results indicate that the CoMFA approach is appropriate for describing nonlinear effects in 3D QSAR studies.

Quantitative structure-activity relationships of the metabolism of drugs by uridine diphosphate (UDP)-glucuronosyltransferase have been investigated. It is observed that most of the variation in the rate of glucuronidation of phenols, thiols, and some other miscellaneous compounds can be accounted for by the lipophilic property of the molecules. The results are consistent with the previous finding with primary and secondary alcohols, and benzoic acids. The optimum lipophilicity for these compounds undergoing metabolism by UDP-glucuronosyltransferase appears to be a log P of 2.

The applicability of a comparative molecular field analysis (CoMFA) method to reproduce and predict the pKa values of 28 clonidine-like imidazoline analogues and 16 2-substituted imidazoles has been investigated with the GRID force field. Molecular fields calculated with an H+ probe and AM1 partial atomic charges produced a correlation with a small standard deviation and a high correlation coefficient with cross validation. It was concluded that the CoMFA treatment of electrostatic effects is suitable for predicting pKa values and thus for the examination of the electronic effects in 3D quantitative structure-activity relationships.

We examined the ability of the comparative molecular field analysis (CoMFA) method to reproduce Hammett σ constants. The dataset includes 49 substituted benzoic acids. Molecular fields calculated with an H + probe and AM1 partial atomic charges produce a good fit and cross-validated estimate of σ. This estimate is more accurate than that found from a CoMFA analysis using charges based on fits to STO-3G electrostatic potential surfaces. It is also superior to that derived from regression analysis of the charges on the atoms. The relationships predicted the σ of 21 of 23 additional compounds to within 0.27 kcal/mol. We concluded that the CoMFA treatment of electrostatic effects is suitable for the examination of 3D quantitative structure-bioactivity relationships

Quantitative structure–activity relationships (QSAR) of the 1-phenyl-3-aminopyrazoline analogues as inhibitors of immune complex-induced inflammation have been studied. The correlation suggests that the overall size of the phenyl substituents are of importance, and bulky groups have negative effects on potency. The negative steric effects are gradually increased from ortho to meta to para positions. The negative steric effects were sometimes altered by the electronic effects of the substituents. Electron-releasing groups on the phenyl ring increased potency, while electron-withdrawing groups decreased it. Ortho substituents, however, have unaccounted for additional deleterious effects described here with an indicator variable. The octanol–water partition coefficient (log P ) and dissociation constants ( pK s ) of the 1-( m -trifluoromethylphenyl)-3-aminopyrazoline analogue have been experimentally determined.

A lead optimization is usually carried out by structure-activity relationship (SAR) and/or quantitative structure-activity relationship (QSAR) studies. One of the assumptions in SAR and QSAR studies is that similar analogs bind to the same binding site in a similar binding mode. One often observes that there are outliers, especially in QSAR. However, most QSAR studies are carried out focusing their attention to the development of QSAR and leave the outliers without much attention. We searched a number of ligand-bound X-ray crystal structures from the protein structure database to find evidences that could indicate a possible source of outliers in SAR or QSAR. Our results show that unusual binding mode could be a source of outliers.

Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.

The technique of comparative molecular modelling of protein structures has been known for some time, and there are a large number of guanine nucleotide-binding protein coupled receptor (GPCR) model structures obtained utilizing this technique. Likewise, a growing number of three-dimensional quantitative structure‐activity relationship (3D QSAR) studies have been described on various GPCR ligands using the Comparative Molecular Field Analysis (CoMFA) methodology (see the chapter by Ki Hwan Kim in this volume for a listing). Nonetheless, there are only a few studies that have utilized both techniques for ligand design. Several explanations are possible for this. The most probable reason might be that there are still many uncertainties in the current GPCR models, even though these GPCR models would be refined as the technique improves and additional experimental data become available. A similar statement can be made for the CoMFA methodology, which was invented for the situations where the 3D structure of macromolecule is not known, and this is where it is most frequently used. However, a growing number of CoMFA studies take advantage of the known 3D structure of macromolecule. A third reason for the small number of studies utilizing both techniques might be that many scientists may be an expert on one methodology but not both. As both the GPCR modelling and CoMFA studies progress, examples of the use of both techniques in a study will certainly grow. In some cases, the experts in the field of protein modelling and three-dimensional quantitative structure‐activity (3D QSAR) studies may cooperate to bring the two together. Certainly, more and more scientists will become familiar with both techniques. The objective of this report is to build a bridge between the two techniques: 3D protein modelling and the 3D QSAR approach of CoMFA, toward the common goal of ligand design. Toward this goal, three examples are described below where both CoMFA and a GPCR model were used in a study. Seven more examples are summarized to examine how the protein structures and CoMFA results were used together in other than GPCRs. 2. G-protein Coupled Receptors

Pyrimido-oxazepine based sub-micromolar inhibitors (2–4) for Aurora and FLT-3 were designed and synthesized. These preliminary results supported the potential use of pyrimido-oxazepines as a versatile template for developing specific kinase inhibitors.

The development of high throughput tissue cytometry capable of mapping gene and protein expression profiles in 3-D with subcellular resolution throughout whole organs of small animals extends bioinformatic analysis to physiology and pathology.

We present a multicolor multiphoton fluorescence microscope with single-photon counting sensitivity. The system integrates a standard multiphoton fluorescence microscope, an optical grating spectrograph operating in the UV-Vis wavelength region, and a 16-anode photomultiplier tube (PMT). The major technical innovation is in the development of a multichannel photon counting card (mC-PhCC) for direct signal collection from multi-anode PMTs. The electronic design of the mC-PhCC employs a high-throughput, fully-parallel, single-photon counting scheme along with a high-speed electrical or fiber-optical link interface to the data acquisition computer. There is no electronic crosstalk among the detection channels of the mC-PhCC. The collected signal remains linear up to an incident photon rate of 10(8) counts per second. The high-speed data interface offers ample bandwidth for real-time readout: 2 MByte lambda-stacks composed of 16 spectral channels, 256 x 256 pixel image with 12-bit dynamic range can be transferred at 30 frames per second. The modular design of the mC-PhCC can be readily extended to accommodate PMTs of more anodes. Data acquisition from a 64-anode PMT has been verified. As a demonstration of system performance, spectrally resolved images of fluorescent latex spheres and ex-vivo human skin are reported. The multicolor multiphoton microscope is suitable for highly sensitive, real-time, spectrally-resolved three-dimensional imaging in biomedical applications.

We present a summary of the three-year Challenge Project (C68), begun in 2001, with the objective of demonstrating a capability to simulate time-dependent six-degree-of-freedom motions of ships in waves and the associated near-field flow using unsteady Reynolds-Averaged Navier-Stokes (RANS) codes. The efforts involved a team of researchers using two state-of-the-art unsteady RANS codes for a progression of building-block simulations at both model- and full-scales and for practical configurations including detailed resolution of propulsors and appendages. The two RANS codes used for this project are UNCLE, developed at the Mississippi State University, and CFDSHIP-IOWA, developed at the University of Iowa. The three-year efforts have successfully demonstrated a capability to simulate coupled pitch/heave motions, coupled pitch/heave/roll motions, maneuvers in the horizontal plane, and near-field wake, including propeller and viscous effects. The predictive capability demonstrated in this project has clearly paved the way for more challenging computations that involve large-amplitude motions in high sea states for a new generation of naval ships, including surface combatant and other future hull forms.

Tissue physiology and pathology can be better understood using two-photon microscopy that allows tissue structure and biochemistry to be assayed on the subcellular level. Histological analysis provides high-resolution tissue characterization and is the only imaging method that can be applied to tissues of arbitrary thicknesses. Scanning confocal microscopy was invented in 1962 by Minsky demonstrating that three-dimensional (3-D) resolved images can be obtained in translucent specimens without physical sectioning. An alternative 3-D imaging technology is two-photon excitation microscopy, which was introduced by Denk, Webb, and coworkers in 1990. The electronic transition of a fluorophore can be induced by the simultaneous absorption of two photons. Depth discrimination is the most important feature of two-photon microscopy. The design of a typical two-photon fluorescence microscope design is based on three basic components: a femtosecond laser system, high-throughput microscope optics, and high-sensitivity detection optoelectronics. An important advantage of two-photon imaging is its suitability for in vivo imaging.

Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.

A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.

Multiphoton microscopy is one of the fastest growing areas in biomedical imaging. The potential of multiphoton excitation was first theorized by Maria GoppertMayer in 1931. Generating three-dimensionally resolved microscopic images based on nonlinear optical excitation was postulated in the 1970s (Gannaway and Sheppard, 1978; Wilson and Sheppard, 1984). The definitive experiment was done by Denk, Webb, and co-workers (1990), who accomplished two-photon, three-dimensional (3D) imaging of biological specimens. Furthermore, they demonstrated 3D localized uncaging and photobleaching using two-photon excitation to trigger a photochemical reaction in a subfemtoliter volume.

In our quest toward the discovery of highly potent and acid-stable motilides, novel 4"-deoxy derivatives of 9-deoxo-6, 9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethyl-6, 9-epoxyerythromycin A (10) and (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethanol-6, 9-epoxyerythromycin A (15) had a pED50 of 8.54 and 8.11 compared to a pED50 of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.

The logarithm of capacity factors (log k ′) previously measured from the reversed-phase high-performance liquid chromatography (RP-HPLC) and the octanol-water partition coefficients (log P ) of a mixed set of substituted benzene, furan, benzofuran, pyrrole, 1-Me-pyrrole, indole, and N -methyl indole derivatives are correlated with the descriptors obtained from their three-dimensional structures using the comparative molecular field analysis (CoMFA) approach. The results provide an example where log k ′ and log P values are calculated directly from the three-dimensional structures for a mixed set of compounds.

Capacity ratio (log k') values, which are a measure of hydrophobicity, were calculated directly from the three-dimensional structures of 17 furans and 54 triazines using the comparative molecular field analysis approach. The H2O probe and the GRID force field, including hydrogen-bond potentials, yielded excellent correlations with the log k' values. Moreover, the predicted values of log k' from 14 additional triazine analogs showed excellent agreement with log k' values reported in the literature. Similar results were obtained for the octanol-water partition coefficients (log P) of 17 furans.

Les phenylguanidines substituees utilisees sont des inhibiteurs competitifs de l'urokinase (UK) avec un Ki micromolaire. Essais sur la plasmine humaine, la thrombine plasmatique, la kallikreine plasmatique, le tPA et la trypsine bovine. Seule la trypsine presente une affinite significative

Anumberof5‐substituted3‐[1‐(2‐benzoxazolyl)hydrazino]‐propanenitrile analogues have been studied as inhibitors of the rat pleural reverse passive Arthus reaction, and quantitative structure–activity relationships (QSAR) of these analogues have been examined. The QSAR equations indicate that hydrophilic substituents at the 5‐position produce more potent compounds, while electron‐releasing groups decrease activity. The results supplement QSAR data we previously obtained from the dermal reverse passive Arthus reaction.

Linear free energy methodology and molecular modelling were used to aid the optimization of the structure of a set of (aminomethylaryloxy) acetic acid esters. Series design strategy based on linear free energy relationships all0 wed the optimization within a small set of analogues of the substituent on the amino group and that on the ester. The amino group tolerates only small substituents, whereas all esters are biologically equivalent. Molecular modelling revealed that the oxyacetate side chain and the atom that bridges the two aromatic rings are in regions in space that forbid large substituents.

Le compose du titre est obtenu via un C-12 O-carbamate (issu lui-meme de l'acylation d'un alcool allylique derive de la O-methyl-6 erythromycine A) qui se cyclise ensuite entre C-11 et C-12 par une reaction de Michael intramoleculaire