Quantitative structure-activity relationships for calmodulin inhibitors

Using the discriminant analysis method, we completely distinguished 24 calmodulin inhibitors in three groups, as classified by Zimmer et al. The resultant discriminant functions distinguished the three groups in terms of positive potential surface area on the side chain, as well as the total and neutral surface areas on the ring in the inhibitor molecules. Group assignment of additional calmodulin inhibitors from other sources was then estimated according to the discriminant functions. The relationship between structure and inhibitory potency on calmodulin-activated phosphodiesterase for group I inhibitors, together with those estimated, was studied using the adaptive least squares method with several parameters dependent on molecular conformations. A "best conformer" was selected for each inhibitor on the basis of quantitative structure-activity relationship (QSAR). The results of QSAR analysis of group I inhibitors showed that hydrophobicity was important for the ring moiety but not for the side chain. The negative potential surface area of the side chain is necessary for activity. It is desirable for the nitrogen atom in the side chain, which is considered the center of the negative potential area, to be located far from the ring moiety. Thus, the ring moiety and side chain may possibly play different roles in interactions with the receptor system.     

Synthesis and structure-activity relationships of o-sulfonamido-arylhydrazides as inhibitors of LL-diaminopimelate aminotransferase (LL-DAP-AT)

Recently, LL-diaminopimelate aminotransferase (LL-DAP-AT), a pyridoxal-5'-phosphate (PLP)-dependent enzyme, was reported to catalyze a key step in the biosynthesis of L-lysine in plants and Chlamydia. Previous screening of a 29,201-compound library against LL-DAP-AT identified an o-sulfonamidoarylhydrazide as a reversible inhibitor with IC(50)～ 5 μM. Structure-activity relationship (SAR) studies based on this lead compound identified key structural features essential for enzyme inhibition and led to slightly improved inhibitors. Preliminary studies on the mode of inhibition of LL-DAP-AT by this class of compounds are also reported.     

Synthesis of human renin inhibitory peptides, angiotensinogen transition-state analogs containing a retro-inverso amide bond

The experimental details for the synthesis of human renin inhibitors are described. In order to avoid metabolic degradation of the Phe-His (P3-P2) amide bond in transition-state analogs, structurally modified acyl residues (P4-P3) were incorporated into the inhibitors. Compound 1a, which contained 2-(1-naphthylmethyl)-3-(N-phenethylcarbamoyl)propionyl residue (P4-P3) with a retro-inverso amide bond, L-histidine, and norstatine isoamylamide residue (P1-P1) as a transition-state mimic, had potent human renin inhibitory activity, and it lowered blood pressure when administered orally to common marmosets.     

Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

Summary Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/K_i), with an explained variance r² of 0.885, and a cross-validated q² of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q² for one component was 0.62 and 0.61, respectively, while r² was 0.674. We demonstrate that the predictive r² based on the mean activity (Y_m) of the training set is misleading, while the test set Y_m-based predictive r² index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.     

Renin inhibitors. II. Synthesis and structure-activity relationships of N-terminus modified inhibitors containing a homostatine analogue.

The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatin analogue, (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid, are described. The compounds having a 3-alkyl (or aryl)sulfonylpropionyl residue at the N-terminus are found to be potent inhibitors which contain two amino acids. (2RS,4S,5S)-N-Isobutyl-5-[N-[(2S)-3-ethylsulfonyl-2-(1- naphthylmethyl)propionyl]-L-norleucyl]-amino-2-ethyl-4-hydroxy-7- methyloctanamide (20) has an IC50 of 0.5 nM against human plasma renin and the oral bioavailability of 20 is 0.73% in rats. Interaction between renin and the N-terminus of 1 and 20 is discussed in molecular modeling studies.     

Synthesis and evaluation of macrocyclic transition state analogue inhibitors for alpha-chymotrypsin

Lactams 1 and 2 are readily formed from acyclic precursors in the presence of trypsin and chymotrypsin, respectively, identifying the macrocyclic ring system as a potential motif for constrained transition state analogue inhibitors of the serine peptidases. Ketone 3 was synthesized and shown to be a modest inhibitor of chymotrypsin (Ki = 220 microM), albeit 4-fold more potent than the acyclic hydroxy acid 25 (Ki = 1.5 mM as a mixture of epimers). A precursor (31) to the amino boronic acid 4 was also prepared; although this derivative was a potent inhibitor of chymotrypsin (Ki = 130 nM) by virtue of the boronic acid moiety, it showed no advantage over the des-amino analogue 32 (Ki = 120 nM), which is not capable of cyclizing.     

Synthesis and structure-activity relationships of fenbufen amide analogs

The previous discoveries of butyl fenbufen amide analogs with antitumor effects were further examined. The amide analogs with 1, 3, 4 and 8 carbons chains were prepared in 70-80% yield. Fenbufen had no cytotoxic effects at concentrations ranging from 10 to 100 μM. Methyl fenbufen amide had significant cytotoxic effects at a concentration of 100 μM. As the length of the alkyl amide side chain increased, the cytotoxic effects increased, and the octyl fenbufen amide had the greatest cytotoxic effect. After treatment with 30 μM octyl fenbufen amide, nearly seventy percent of the cells lost their viability. At the concentration of 10 μM, fenbufen amide analogs did not show cytotoxicity according to the MTT assay results. The NO scavenging activities of the fenbufen amide analogs were not significantly different from those of fenbufen.     

Three-dimensional quantitative structure-activity and structure-selectivity relationships of dihydrofolate reductase inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling using comparative molecular similarity indices analysis (CoMSIA) was applied to a series of 406 structurally diverse dihydrofolate reductase (DHFR) inhibitors from Pneumocystis carinii (pc) and rat liver (rl). X-ray crystal structures of three inhibitors bound to pcDHFR were used for defining the alignment rule. For pcDHFR, a QSAR model containing 6 components was selected using leave-10%-out cross-validation (n= 240, q2 = 0.65), while a 4-component model was selected for rlDHFR (n= 237, q2 = 0.63); both include steric, electrostatic and hydrophobic contributions. The models were validated using a large test set, designed to maximise its diversity and to verify the predictive accuracy of models for extrapolation. The pcDHFR model has r2 = 0.60 and mean absolute error (MAE) = 0.57 for the test set after removing 4 outliers, and the rlDHFR model has r2 = 0.60 and MAE = 0.69 after removing 4 test set outliers. In addition, classification models predicting selectivity for pcDHFR over rlDHFR were developed using soft independent modelling by class analogy (SIMCA), with a selectivity ratio of 2 (IC50,rlDHFR/ IC50,pcDHFR) used for delimiting classes. A 5-component model including steric and electrostatic contributions has cross-validated and test set classification rates of 0.67 and 0.68 for selective inhibitors, and 0.85 and 0.72 for unselective inhibitors. The predictive accuracy of models, together with the identification of important contributions in QSAR and classification models, offer the possibility of designing potent selective inhibitors and estimating their activity prior to synthesis.     

Angiotensin-converting enzyme inhibitors: synthesis and structure-activity relationships of potent N-benzyloxycarbonyl tripeptide inhibitors

A new series of gamma-D-Glu-containing N-benzyloxycarbonyl (Z) tripeptide inhibitors of angiotensin-converting enzyme (ACE) was synthesized. The effect of varying the antepenultimate amino acid residue in this series on the biological activity was studied. Introduction of Lys and Orn residues at the P1 position provided the most potent inhibitors, 25a and 25b (IC50: 3.5 and 4.9 x 10(-9) M, respectively), which exhibited an oral antihypertensive activity. This result suggests that basic amino acid residues at the P1 position play an important role in binding with the S1 subsite of ACE in this series. Oral antihypertensive activity of selected compounds was evaluated.     

Renin inhibitors. I. Synthesis and structure-activity relationships of transition-state inhibitors containing homostatine analogues at the scissile bond.

The synthesis and structure-activity relationships of transition-state renin inhibitors containing the homostatine analogues at the scissile bond are described. These inhibitors incorporate the amino acid side chains corresponding to positions 7-12 (P4-P2') of angiotensinogen. Ethyl, 2-hydroxyethyl and 3-hydroxypropyl groups at position 2 of the homostatine analogues (P1') are more effective for increasing potency than the isopropyl group. A combination of residues at P1, P3 and P4 is important for potency and this result suggests that S1, S3 and S4 form a huge hydrophobic core together in renin.     

Exploring structure-activity relationships of tricyclic farnesyltransferase inhibitors using ECLiPS libraries

The development of structure-activity relationships (SARs) relating to the function of a biological protein is often a long and protracted undertaking when using an iterative medicinal chemistry approach. High throughput screening of ECLiPS (Encoded Combinatorial Libraries on Polymeric Support) libraries can be used to simplify this process. In this paper, we illustrate how a large ECLiPS library of 26,908 compounds, based on a tricyclic core structure, was used to define a multitude of SARs for the oncogenic target, farnesyltransferase (FTase). This library, FT-2, was prepared using a split-and-pool approach in which small molecules are constructed on resin that contains tag/linker constructs to track the synthetic process [1-5] Highly defined SARs were produced from this screen that enhanced our understanding of FTase binding site interactions. The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line.     

Capturing structure-activity relationships from chemogenomic spaces

Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for a large number of different targets, have been investigated for their usefulness in automated structure-activity relationships (SAR) extraction. SAR tables were constructed by assembling similar structures around each query structure that have an activity record for a particular target. Quantitative series enrichment analysis (QSEA) was applied to these SAR tables to identify trends and to transform these trends into topomer CoMFA models. Overall more than 1700 SAR tables with topomer CoMFA models have been obtained from the ChEMBL, PubChem, and ChemBank databases. These models were able to highlight the structural trends associated with various off-target effects of marketed drugs, including cases where other structural similarity metrics would not have detected an off-target effect. These results indicate the usefulness of the QSEA approach, particularly whenever applicable with public databases, in providing a new means, beyond a simple similarity between ligand structures, to capture SAR trends and thereby contribute to success in drug discovery.     

Synthesis and novel structure-activity relationships of potent sansalvamide A derivatives

Synthesis of twelve Sansalvamide A derivatives and their SAR against colon cancer (HT-29).     

L-Enantiomers of transition state analogue inhibitors bound to human purine nucleoside phosphorylase

Human purine nucleoside phosphorylase (PNP) was crystallized with transition-state analogue inhibitors Immucillin-H and DADMe-Immucillin-H synthesized with ribosyl mimics of l-stereochemistry. The inhibitors demonstrate that major driving forces for tight binding of these analogues are the leaving group interaction and the cationic mimicry of the transition state, even though large geometric changes occur with d-Immucillins and l-Immucillins bound to human PNP.     

Structure activity relationships of new inhibitors of mammalian 2,3-oxidosqualene cyclase designed from isoquinoline derivatives

We have designed more potent inhibitors from the previously reported LF 05-0038, a 6-isoquinolinol based inhibitor of 2,3-oxidosqualene cyclase (IC50: 1.1 microM). Replacement of the 3-OH group by various 3-substituted amino groups, and modification of the alkyl chain borne by the endocyclic nitrogen led to inhibitors with IC50 in the range of 0.15 to 1 microM. In a second step, opening of the bicyclic ring system afforded the corresponding aminoalkylpiperidines which were slightly more potent. Finally, introduction of suitable aromatic containing moieties on the piperidine nitrogen yielded very potent inhibitors such as 20x (IC50 = 18 nM) easy to synthesize and achiral. The recent availability of the crystal structure of squalene-hopene cyclase allowed us to construct a three-dimensional (3D) model of the related 2,3-oxidosqualene cyclase (OSC) which was tentatively used to describe the possible mode of binding of our compounds and which can be useful for designing new inhibitors.     

Glycosidase inhibitors as conformational transition state analogues

A method for estimating the conformational similarity between hexopyranose rings is presented and used to probe the behaviour of various glycosyl hydrolase inhibitors as conformational transition state analogues.     

Synthesis and structure-activity relationships of potent 1-(2-substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors

Dipeptidyl peptidase IV (DPP-IV) inhibitors have attracted attention as potential drugs for use in the treatment of type 2 diabetes because they prevent the degradation of glucagon-like peptide-1 (GLP-1) and extend its duration of action. We previously reported that 2-cyano-4-fluoropyrrolidines act as potent DPP-IV inhibitors and have been modifying the 1-position of pyrrolidine to obtain more useful inhibitors. An L-tert-butylglycine derivative was found to be a stable and potent DPP-IV inhibitor that exhibits a glucose lowering effect in vivo. Here, we report the synthesis of and biological data on the aforementioned derivatives.