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Multiple physical properties are simultaneously optimized in the development of functional materials. However, it is difficult to satisfy all of the demand for physical properties because trade-offs are among multiple characteristics. To overcome this problem, we propose machine learning incorporating the concept of deviation value in this study. In our case, we optimized the monomer mixing ratio in polyurethane film by predicting an index that integrates multiple physical properties. We compared the number of trials required for improving the performance of thin films between that performed by the experimentalist and that by machine learning. As a result, we confirmed that the artificial intelligence (AI) model successfully found the high-performance films by a lower number of trials.

Design processes of functional polymers were accelerated by adopting the Bayesian optimization; the number of trials in the process was substantially reduced. The optimization process was more than forty time accelerated to find out the target polymer compared to the random selection. The optimization efficiency was found to be successfully improved by utilizing the standard deviation of predicted probability distribution of objective function. The performance of the method was robust for dataset size in the analysis; the target polymer could be found even for a small training dataset. The proposed method is a promising tool for the high-performance polymer design, and a wide range of its applications will be expected in the polymer industry.

Evaluating airborne pollen concentrations is important for the understanding of the spatiotemporal dispersion of pollen grains. Using two identical pollen monitors in parallel, we performed two experiments in order to study the influences of a) the physical characteristics (orientation) of the air inlet and b) the presence of obstacles in proximity to the monitors on airborne pollen concentration data. The first experiment consisted of an evaluation of airborne pollen concentrations using two different types of orifices; 1) a vertically oriented inlet and 2) a wind vane intake, both attached to the same type of automatic pollen sampler. The second experiment investigated the relationship between vertical wind speed and horizontal wind direction around an obstacle with the goal of studying the impact of micro-scale wind on pollen sampling efficiency. The results of the two experiments suggest that the wind path near an obstacle might be redirected in a vertical direction before or after the wind flows over the obstacle, which causes measurement errors of airborne pollen concentrations that are proportional to the vertical wind speed, especially when a vertically oriented inlet is used.

The development of a simple and automatic pollen measurement methodology is required to manage allergic problems caused by airborne pollen. We developed a device and algorithm to automatically monitor airborne pollen by using basic laser optics technology. The device measures the sideward and forward scattering intensities of laser light from each particle. Because this device provides detailed temporal variation in the pollen concentration, the dispersal dynamics of airborne pollen can be effectively analyzed. We compared the pollen counts obtained with the automated method and standard Hirst-type method. Scatter-plot graphs were constructed of the forward and sideward scattering intensities of the observed particles. An extract window methodology was used to estimate the concentrations of the major allergenic pollens. The extract window parameters were obtained for major types of allergenic pollen. The results suggest the possibility of developing a device for monitoring several types of airborne pollen simultaneously. We determined the standard extract window to be used for estimating the concentration of all types of airborne pollen together. A field experiment was performed to evaluate the automated monitoring system with the standard extract window. The estimated temporal variation pattern of the total airborne pollen concentration agreed well with the observed temporal variation pattern for the whole pollen season. The pollen monitor was able to estimate the overall features of seasonal changes in the total airborne pollen concentration.

Since the first paper for the QSAR procedure was published in 1962, a number of agrochemical QSAR studies have been accumulated. Among them, some studies were to construct models to design new compounds of the improved activity profiles. Others were to search for a clue for molecular mechanisms of action and/or physicochemical backgrounds for some “compulsory or favorable” substructures and substituents within the compound series. In this article, some examples of studies from these two categories are reviewed.

Key Clinical Message Central diabetes insipidus (CDI) results from a deficiency of arginine vasopressin (AVP) secretion. It is treated by replacement therapy with the synthetic AVP analogue desmopressin. To prevent heart failure in patients with CDI accompanied by cardiac dysfunction, controlling sodium and water intake is essential, using the minimum effective dose of desmopressin.

Background Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors. Hypertension secondary to pheochromocytoma is often paroxysmal, and patients occasionally present with sudden attacks of alternating hypertension and hypotension. Spontaneous, extensive necrosis within the tumor that is associated with catecholamine crisis is an infrequent complication of adrenal pheochromocytoma, but its pathogenesis remains unclear. Case presentation A 69-year-old Japanese man developed acute-onset episodic headaches, palpitations, and chest pains. During the episodes, both marked fluctuations in blood pressure (ranging from 40/25 to 300/160 mmHg) and high plasma levels of catecholamines were found simultaneously. Radiological findings indicated a 4-cm left adrenal pheochromocytoma. These episodic symptoms disappeared within 2 weeks with normalization of plasma catecholamine levels. Two months later, the patient underwent adrenalectomy. Microscopic examinations revealed pheocromocytoma with a large central area of coagulative necrosis. The necrotic material was immunohistochemically positive for chromogranin A. Granulation tissue was adjacent to the necrotic area, accompanied by numerous hemosiderin-laden macrophages and histiocytes with vascular proliferation. Viable tumor cells, detected along the periphery of the tumor, demonstrated pyknosis, and the Ki-67 labeling index was 2 % in the hot spot. No embolus or thrombus formation was found in the resected specimen harboring the whole tumor. The Pheochromocytoma of the Adrenal gland Scaled Score was 2 out of 20. The patient’s postoperative course was unremarkable for > 7 years. Conclusions Presumed causal factors for the extensive necrosis of adrenal pheochromocytoma in previously reported cases include hemorrhage into the tumor, hypotension induced by a phentolamine administration, embolic infarction, high intracapsular pressure due to malignant growth of the tumor, and catecholamine-induced vasoconstriction. In the present case, histopathological and clinical findings suggest that under conditions of chronic ischemia due to catecholamine-induced vasoconstriction, an acute infarction occurred after sudden attacks of alternating hypertension and hypotension. Over the subsequent 2 weeks, repetitive massive release of catecholamines from the infarcts into circulation likely accelerated infarction progression by causing repeated attacks of alternating hypertension and hypotension and resulted in the large necrosis. This case highlights the need for physicians to consider acute spontaneous tumor infarction accompanying episodic catecholamine crisis as a rare but severe complication of pheochromocytoma.

To examine the relationship between the scavenger receptor A (SRA) index (the number of SRA+ cells observed in 10 high power fields of peripheral blood (PB) smear samples; normal upper limit

Human immunodeficiency virus type 1 protease (HIV-1 PR) is an essential enzyme for the replication cycle of HIV-1. HIV-1 PR inhibitors have been extensively investigated as anti-AIDS drugs. For developments of HIV-1 PR inhibitors more promising than those utilized at the moment, the construction of reliable QSAR models that can elucidate the inhibitory mechanism as consistently as possible should be one of the most significant issues. Garg, Kurup, and their groups published comprehensive QSAR studies using past structure-activity data for HIV-1 PR inhibitors, and summarized some physicochemical structural factors of inhibitors that govern variations in the inhibitory activity for various structural types. There seem to exist much to be clarified further, especially for effects of electronic structure of inhibitors. It is also expected to incorporate structural and physicochemical information about the enzyme protein into the QSAR model. In this article, we reviewed our own QSAR study on a series of cyclic urea inhibitors with newly proposed QSAR descriptors. We performed molecular dynamics simulations of HIV-1 PR-inhibitor complexes to provide the accurate geometry to the fragment molecular orbital (FMO) calculations as well as to the estimation of an accessible surface area descriptor for inhibitors and amino acid residues. With the FMO procedure to cover full electronic feature of three-dimensional structure of protease-inhibitor complexes, we derived electronic descriptors for inhibitors and amino acid residues. The successful results are believed to provide a new insight into QSAR and understanding of binding mechanism of inhibitors with HIV-1 PR at atomic and electronic levels.

To investigate the efficacy and safety of bepotastine, we conducted a randomized, investigator-blind, placebo-controlled and parallel study to evaluate the allergic symptoms and the cognitive function of the subjects with Japanese cedar (JC) pollinosis in response to JC pollen exposure in an artificial exposure chamber.Twenty-four volunteers with JC pollinosis were enrolled in this study. The subjects were randomly divided into two groups: a bepotastine group and a placebo group (12 subjects each). Subjects received either a 10-mg bepotastine OD (orally disintegrating) tablet or a placebo 10 min before entering the chamber for a 3-h exposure. The nasal and ocular symptoms were evaluated by each patient at regular intervals. The amount of nasal discharge was measured and the number of sneezes recorded. To evaluate the cognitive function, a digit cancellation test (D-CAT), in which the subjects have to eliminate certain numbers within a fixed time, was conducted.Twelve subjects in the placebo group developed nasal and/or ocular symptoms, whereas six subjects in the bepotastine group showed none of the symptoms during exposure. Mean secretion weights and number of sneezes were significantly lower in the bepotastine group than in the placebo group. In D-CAT, no deterioration of work performance was observed in the bepotastine group. No adverse effects were observed in either group.Bepotastine treatment is effective and well tolerated in patients with allergen-induced symptoms exposed to JC pollen in an exposure chamber.

One hundred Suc-X-Y-Ala-pNA peptides: (Suc: succinyl, pNA: p-nitroanilide, X, Y: Gly, Ala, Val, Leu, Ile, Phe, Pro, alpha-aminobutyric acid, norvaline, norleucine) were synthesized and their reaction constants with porcine pancreatic elastase (Km, kcat and kcat/Km) were determined. These reaction constants were quantitatively analyzed using the Free-Wilson/Fujita-Ban method. The contribution of amino acid side chains to the reaction constants Km, kcat and kcat/Km, expressed logarithmically, was found to be additive. On the other hand, 19 elastase inhibitors of the general formula CF3CO-X-Y-Ala-pNA (X,Y: ten amino acids) were synthesized, and their inhibition constants were compared with the Michaelis constant for the corresponding substrates and analyzed using free-energy-related substituent constants. In the analysis of amino acid side chains in the Y position, the Ki value of the inhibitor was generally correlated to the Km value of the substrate, which corresponded to the inhibitor, thus confirming the validity of the equation. log(1/Ki) = 1.271 log(1/Km) + 4.831 This study may serve as a prototypical approach to unraveling structure-activity relationships of peptide substrates and inhibitors of medicinal or agricultural importance.

Background: An artificial exposure chamber (OHIO Chamber), which allows dispersal of a fixed concentration of Japanese cedar (JC) pollen under stable conditions, was constructed. This study was conducted to identify the exposure conditions assuring validity of the clinical tests conducted using this chamber. Methods: Twenty-four adult patients with JC pollinosis were exposed to different concentrations of JC pollen: 0 (only during the summer period), 4,000, 8,000 and 12,000 grains/m3, and the nasal and ocular symptoms were self-assessed during a 4-hour period of exposure. The amount of nasal discharge was measured and the sneezing frequency was recorded. This study was conducted twice during the summer and winter periods, i.e. non-pollen seasons. The reproducibility of the symptoms between the two seasons was assessed. Results: None of the subjects developed any symptom at the pollen concentration of 0 grains/m3. No significant differences in the time to the onset of symptoms were found between the summer and winter study, regardless of the pollen concentration. There were no significant differences between the summer and winter study in the total symptom score and total nasal symptom score at any pollen concentration, suggesting the very favorable reproducibility of symptoms. Conclusions: Efficient and reproducible results are obtained in patients exposed to JC pollen in the OHIO Chamber. The results suggest the conditions of JC pollen exposure have scientific validity and the OHIO Chamber has the potential to contribute significantly to basic and clinical studies of JC pollinosis.

Airborne pollen is important in relation to the social issues of pollinosis and of the environmental effects of genetically modified plants. Existing methods for pollen counting involve counting and classifying the grains that adhere to a sampling surface, requiring much time and skilled labor. We therefore have developed a method of automatically monitoring pollen, using a laser-optics instrument. In this instrument, the sideways and forward scattering of laser light by each particle is recorded in real time for computer processing. A field experiment was conducted in 2005, comparing our method with that of the older Hirst method. A scatter plot was made of the forward scattering vs. the sideways scattering for each particle. An algorithm was developed to find the optimum rectangular region of the plot for each type of pollen, and a count of points inside this region was taken as the count for that type of pollen. For the three most common types of pollen found in the field test (Urticaceae, Poaceae, and Ambrosia), the daily counts from this algorithm were compared with the daily counts from the Hirst-type (Burkard) sampler. There was a very high correlation (determination coefficient approximately 0.8) between the results of the two methods.

Background: Definitive substrates for the measurement of pancreatic lipase activity in human serum have not been conclusively identified owing to poor aqueous solubility and nonspecific susceptibility of substrates with existing methods. Thus, it is still important to propose new substrates for robust lipase measurements. Methods: Reaction conditions were studied for a lipase method using newly synthesized 2,3-dibutyrylthio-1-propyl oleate as the substrate and 5,5′-dithio-bis-(2-nitro-benzoic acid) as the chromogen. Results: Optimum conditions, using colipase and Mg++ in aqueous hexamethyl phosphoric triamide medium at pH 9.2, were defined. The substrate was highly selective to pancreatic lipase. The reaction increased linearly with lipase concentrations up to 500 U/l. The reference interval of serum lipase concentrations was 21.5–65 U/l. Using the Passing–Bablok regression analysis, the present assay shows a slope of 0.414, an intercept of − 2.4 U/l, and r-value of 0.992 in the comparison with the chromogenic method using the 6-methylresorufin ester of 1-O,2-O-dilauryl-rac-glycero-3-glutaric acid as the substrate. Conclusion: Because of the simple composition of the reagents, the proposed procedure may represent a significant advancement in the commercially available methods for pancreatic lipase determination.

Friedel–Crafts-type reaction of p -xylene with γ-butyrolactone or vinylacetic acid over H 4 SiW 12 O 40 supported on SiO 2 have been investigated with different loadings of H 4 SiW 12 O 40 . The catalytic performance of H 4 SiW 12 O 40 /SiO 2 have been compared with those of typical solid acid catalysts such as zeolites, ion-exchanged resins, and binary oxides. H 4 SiW 12 O 40 supported on SiO 2 was superior in activity and selectivity to 5,8-dimethyl-α-tetralone compared to other catalysts for the reaction between p -xylene and γ-butyrolactone. SiO 2 -supported H 4 SiW 12 O 40 also was efficient for the formation of 3,4,7-tetramethyl-α-indanone from p -xylene and vinylacetic acid. The formation of 5,8-dimethyl-α-tetralone is extremely sensitive to the load of H 4 SiW 12 O 40 on SiO 2 , reaching a maximum at approximately 30 wt%, due to the change in the acid amount of the outermost surface as determined by benzonitrile-temperature programmed desorption. By analogy with reaction between 1,3,5-trimethylbenzene and γ-butyrolactone, the reaction pathway involves initial alkylation of p -xylene with γ-butyrolactone, followed by intramolecular acylation to 5,8-dimethyl-α-tetralone, which was supported by quantum calculations of γ-butyrolactone and protonated γ-butyrolactone.

A 35-year-old Japanese woman was admitted with coma following flu-like symptoms. She was diagnosed with diabetic ketoacidosis and fulminant type 1 diabetes (FT1D) and received intravenous infusion of insulin and saline. The next day, the ketoacidosis disappeared, and she recovered consciousness. However, extensive ST-segment elevations in the electrocardiogram appeared with a positive troponin test, and the patient developed pulmonary edema on day 3. An echocardiogram showed globally reduced wall motion of the left ventricle and mild pericardial effusion. Despite medical therapy with intravenous furosemide, carperitide, and catecholamines, her cardiac function deteriorated rapidly, with the left ventricular ejection fraction decreasing to 26% within 7 hours, and progressed to cardiogenic shock that afternoon. The patient received mechanical circulatory support for 4 days with intra-aortic balloon pumping and percutaneous cardiopulmonary support, and recovered fully from circulatory failure. A paired serum antibody test showed a significantly elevated titer against parainfluenza-3 virus, indicating a diagnosis of fulminant viral myocarditis. She was discharged on multiple daily insulin injection therapy, and her subsequent clinical course has been uneventful. In summary, we present a case of concurrent FT1D and fulminant viral myocarditis. Parainfluenza-3 viral infection was confirmed serologically and was considered to be a cause of both the FT1D and fulminant myocarditis.

To analyze the log Psol/w values (sol: n-octanol or chloroform, w: water) in the framework of the molecular orbital (MO) procedure, we selected solute descriptors such as the solvation energy difference between aqueous and organic solvent phases and the “surface” area of solute molecules to which water molecules are accessible. The solvation energy of solute molecules in their minimum free-energy conformation was calculated using the ab initio self-consistent reaction field-MO method with the conductor-like screening model. The experimentally measured log Psol/w value of various solutes except for those of amphiprotics was shown to be analyzable reasonably well by the MO model with additional descriptors for the hydrogen-bonding patterns in the solute–solvent interactions. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2681–2697, 2004

This workshop has been organized to cover various quantitative structure-activity relationship (QSAR) and computer aided procedures currently carried out for the prediction of the endocrine activity of unknown compounds. Each of the procedures has own scope as well as limitations. It seems inappropriate to consider that a single quantitative prediction model derived from each of these procedures could solve the entire issue. Because the model building is highly dependent on the data/knowledge about endocrine activity of a large number of existing compounds accumulated to date and the data/knowledge are growing constantly, the model has a destiny to be amended “forever ”as the structure-activity data of newly synthesized compounds are accumulated. The skepticism about in silico and QSAR procedures put forward in the past is likely to be cleared at least to some extent if not entirely by participating in this workshop.

N-Isobutyl-N-(4-substituted benzyl)-4-halo-2-pentenamide 類はヒエに対し顕著な光要求性の除草活性を示す. ワタの幼植物およびそれより調製した酵素標品, ならびに培養した単細胞藻類を用いたアッセー系により, 殺草のメカニズムの解明を試み, 一連の供試化合物は明らかに protoporphyrinogen oxidase (PPO) 阻害活性を示したが, 植物毒性の強度変化は, むしろクロロフィル生合成阻害活性の強度変化によく対応した. したがって, 本系列の化合物の植物毒性には, PPOの阻害以外にクロロフィル生合成のほかの段階の阻害が重なっていることが示唆された.

Larvicidal activity against the Colorado potato beetle Leptinotarsa decemlineata (Say) was measured for a series of N-tert-butyl-dibenzoylhydrazines having various substituents on the benzoyl (A-ring) moiety nearer to the tert-butyl group, with the other benzoyl (B-ring) moiety being unsubstituted. The effects of these substituent on the larvicidal activity were analyzed using classical quantitative structure-activity relationship (QSAR) procedures. The effects of substituents on the A-ring moiety on larvicidal activity were entirely different from those against the lepidopteran rice stem borer Chilo suppressalis (Walker) previously reported. Position-specific steric and hydrophobic effects, as well as certain substitution patterns, were likely to participate in modifying the larvicidal activity. The activity of para-substituted compounds was generally lower than that of un-, ortho- and meta-substituted compounds. Most multi-substituted compounds showed an activity equivalent to or lower than that of the unsubstituted compound. Among 46 compounds tested, the 2-sec-butoxy analogue was most potent against L decemlineata, although this compound had previously been shown to be only weakly active against C suppressalis.

The three-dimensional “bioactive” conformations of various types of pyrethroid insecticides were deduced from among optimized conformations which were generated on the basis of the exhaustive conformational exploration of the reference compound, MTI-800. A “folded” rather than an “extended” conformation was proposed to be the “bioactive structure” of pyrethroid molecules included in this study. The folded “bioactive” structures were further analyzed in terms of molecular (dis)similarity indices to elucidate the effect of the “local” structural variations on the activity. The results indicate that the overall bioactive conformation as well as the local 3D similarity of the molecule are important in governing the potency variations in the insecticidal activity.

Insecticidal activity against the Colorado potato beetle, Leptinotarsa decemlineata, was measured for a series of substituted N-tert-butyl-dibenzoylhydrazines, in which one of the benzoyl moieties closer to the tert-butyl group was fixed as being 2-chloro-substitued and the other variously substituted singly or doubly. The effects of substituents on the activity were quantitatively analysed using the classical quantitative structure–activity relationship (QSAR) procedure. The activity against the Colorado potato beetle increases with the molecular hydrophobicity. In addition, various types of steric effect are at work, depending upon the positions. Hydrogen-bonding acceptor substituents at the para position enhance the activity. There seem to be threshold (or optimum) values, albeit position-dependent, in the molecular hydrophobicity, above which the activity starts to decrease. This biphasic contribution of the molecular hydrophobicity to activity against coleopterous larvae is the most conspicuous difference in substituent effects from those found for similar compounds against lepidopterous pest insects, and may be the basis of the variations in the activity spectrum for certain compounds in this series. The introduction of bulkier substituents into the meta- and para-positions of the benzene ring, apart from the tert-butyl group, is unfavorable to activity. LD50 values against Colorado potato beetle larvae of methoxyfenozide (RH-2485) and tebufenozide (RH-5992) were in the order of 10−7 mol per insect, whereas those of RH-5849, and halofenozide (RH-0345) were very low, 10−9–10−10 mol per insect being selective to the coleopterous larvae. © 1999 Society of Chemical Industry

タイヌビェ, Echinochloa oryzicola に対するN-アルキル-N-(4-置換ベンジル)-4-クロロ-2-ペンテンアミドの除草活性を評価し, アミド部位に於けるN-アルキル基及びベンジル基のベンゼン環置換基と除草活性との関係を物理化学パラメーターを用い定量的に解析した. 除草活性はアミド部位に於けるトータルな疎水性とパラボリックな関係であることが示された. また, ベンゼン環上置換基の電子吸引性及び水素結合受容性が除草活性に重要であることが判明した.

Ring-substituted dibenzoylhydrazines are well known as nonsteroidal ecdysone agonists that cause precocious larval molt leading to death. Among them, tebufenozide (RH-5992) is used in practice as insecticide to control lepidopteran pests selectively. Recently, a new dibenzoylhydrazine, methoxyfenozide (RH-2485), with a higher activity for Lepidoptera, has been discovered. To obtain insight into the molecular mechanisms involved in the insecticidal selectivity of the dibenzoylhydrazine family, we measured the in vivo toxicity of these dibenzoylhydrazines against larval stages of the beet armyworm, Spodoptera exigua, and their action on in vitro cultured imaginal discs. We found that both nonsteroidal ecdysone agonists induced premature and lethal molting, and caused the same effect as 20-hydroxyecdysone in vitro. Furthermore, we measured the larvicidal activity against S. exigua of a series of dibenzoylhydrazines, in which ring-substituents were varied in a range of halogen, lower alkyl, OCH3, SCH3, Ph, CN, NO2, and CF3. The substituent effects on the larvicidal activity against S. exigua were very similar to that for another lepidopteran insect species Chilo suppressalis, suggesting that the molecular mechanism of action of these compounds is similar within both lepidopteran species. Arch. Insect Biochem. Physiol. 41:42–53, 1999. © 1999 Wiley-Liss, Inc.

A new procedure for 3D-QSAR analyses is proposed. The steric and electrostatic potential indices are calculated/estimated at lattice points, but the indices are manipulated to be assigned to superposed molecular regions defined by the Voronoi polyhedral division. The number of the descriptors from which latent variables are extracted by the partial least squares procedure is much lower than that used in the SYBYL-CoMFA. As the steric potential function, the hard-sphere model was used instead of the Lennard-Jones equation. The partial least squares procedure was applied to steric and electrostatic field variables, separately, so as to make the physicochemical meaning of the latent variables easily understandable. The procedure is shown to work almost equivalently with or even better than the classical QSAR as well as the conventional 3D-QSAR such as the CoMFA.

Isobutyranilidoxime meta-phenoxybenzyl ethers and related compounds were synthesized. Their insecticidal activities measured against Periplaneta americana by injection were lower than that of phenothrin by factors of at least 1/60. However, some compounds were comparable to or only slightly less potent than phenothrin and tetramethrin in miticidal activity tested by a contact method against Dermatophagoides farinae, D. pteronyssinus and Tyrophagus putrescentiae.

The activity of a number of O-(4,6-dimethoxypyrimidin-2-yl)salicylic acids and their thio analogs inhibiting acetolactate synthase (ALS) preparation was measured. The effects of substituents on the salicylic-benzene ring on the inhibitory activity were analyzed quantitatively with physicochemical substituent parameters. For 6-substituted (thio)salicylic acids, the activity was shown to vary parabolically with the 'intramolecular' steric parameter (E g ). In addition, the higher steric dimension of substituents in terms of the STERIMOL width or length parameter lowered the activity. The field-inductive electron-withdrawing property of the 6-substituents in terms of the Swain-Lupton-Hansch F was favorable for the activity of salicylic acid series. In 5-substituted salicylic acids, the activity was increased by electron-donating substituents with smaller size. The relationships between ALS inhibitory and herbicidal activities were also analyzed with some weed species. Both pre- and post-emergence activities against barnyard grass, Echinochloa crus-galli, were linearly related to the ALS inhibitory activity after allowing for the hydrophobic factor that may contribute to the transport processes. Those against two broad-leaved weed species, Polygonum convolvulus and Abutilon theophrasti were linearly related to the in-vitro activity with no significant participation of the hydrophobic factor.

Quantitative structure-activity relationships for insecticidal activity (against houseflies) and competitive activity against a specific [ 35 S]tert-butyl-bicyclophosphorothionate binding (to rat brain membranes) of some picrotoxinin-type 4-aminobutyric acid antagonists, including γ-BHC, endosulfan, bicyclophosphates, dioxatricyclododecenes and related compounds, were examined three-dimensionally using comparative molecular field analysis (CoMFA). The antagonists were classified into two series according to their molecular shapes: i.e. whether their structure was 'linearly' extended beyond the 'mast-head' position of the 'boat-like' skeletons (series 1) or not (series 2). The CoMFA showed that the slopes in steric and electrostatic fields around the molecule were significant for both series in governing the potency variations in insecticidal and binding activities. Hydrophobicity, a possible factor controlling transport behaviour of compounds, was significant in governing variations in insecticidal activity, but not for the case of the rat membrane binding. Assuming that there is a slight topological difference between series 1 and 2 compounds in terms of the mode of binding with the housefly receptor site, the insecticidal activity was analysable with a single equation for the combined set of compounds, but the rat membrane binding was not. The sterically and electrostatically favourable regions surrounding the molecular series indicated by CoMFA were roughly located at positions so as to interact with the binding subsites on the receptors proposed previously.

New successful applications of the Hansch-type traditional QSAR to key steps in designing novel bioactive compounds are reviewed. Studies for a benzhydrylbenzylpiperazine antimigraine agent (lomerizine), azole-type agricultural fungicides (metconazole and ipconazole), and a biphenylyloxobutanoic acid antiinflammatory agent (flobufen) were taken as the examples. Structural optimizations were nicely made by using the QSAR information sometimes along with findings obtained from 3D molecular modelling studies and/or hypotheses proposed for metabolic fates. The two azole fungicides were launched in 1994. The antimigraine and antiinflammatory agents are expected to be commercialized soon.

The authors describe an innovative approach for designing novel inhibitors. This approach effectively integrates the emerging chemogenomics concept of target-family-based drug discovery with bioanalogous design strategies, including privileged structures, molecular frameworks as well as bioisosteric and bioanalogous/isofunctional modifications. The authors applied this method in the design of selective inhibitors of matrix metalloproteases (MMPs), also referred to as matrixins, on the basis of a unique analysis of the ligand-target knowledge base, the 'matrixinome'. For this analysis, the authors created an annotated MMP database containing ∼ 300 inhibitors with their published activity profile. The ligand space was then arranged into a lead evolution tree, where the substructural transformations in each virtual step led to marked changes in the activity pattern. This allowed subtype-specific privileged fragments to be extracted as well as modifications, which improve activity and/or selectivity. Furthermore, the compounds with the preferred activity profile were correlated with sequence homology as well as binding site similarity within the target family, thereby leading to the identification of substructural modifications that turn non-selective, biohomologous structures into selective inhibitors. The matrixinomic application of the authors' approach, therefore, provides an example of how the combination of ligand space knowledge with sequence-related data can radically improve the outcome of the lead optimisation process to achieve higher selectivity within a given target family.