Arup Ghose

• Teva Pharmaceutical Industries Ltd.

At the drug discovery stage, it is important to understand the design concepts of a CNS drug compared to a non-CNS drug. Previously we published on ideal CNS drug space and defined in detail the physicochemical property space distribution of CNS and non-CNS oral drugs, the application of radar charting (a graphical representation of multiple physic...

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal...

A series of potent anaplastic lymphoma kinase (ALK) inhibitors based on a 7-amino-6-chloro-3H-imidazo[4,5-b]pyridine scaffold were identified through rational design from a 5-chloro-2,4-diaminopyrimidine pharmacophore, maintaining key binding elements, favourable lipophilic interactions and orienting the side chains into favoured trajectories. Impo...

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidi...

The central nervous system (CNS) is the major area that is affected by aging. Alzheimer's disease (AD), Parkinson's disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood-brain barrier (BBB) penetration is often considered a significant hurdle in the CNS...

A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13...

The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign...

Anaplastic lymphoma kinase (ALK) is transmembrane receptor tyrosine kinase, with oncogenic variants that have been implicated in ALCL, NSCLC and other cancers. Screening of a VEGFR2-biased kinase library resulted in identification of 1 which showed cross-reactivity with ALK. SAR on the indole segment of 1 showed that a subtle structural modificatio...

A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Dysregulation of the anaplastic lymphoma kinase (ALK) is implicated in a variety of cancers. A series of tetrahydropyrido[2,3-b]pyrazines was constructed as ring-constrained analogs of a known aminopyridine kinase scaffold. Chemistry was developed to rapidly elaborate the SAR, structural elements impacting ALK inhibitory activity were exploited, an...

Abnormal expression of constitutively active anaplastic lymphoma kinase (ALK) chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) is well established. Recent studies with small molecule kinase inhibitors have provided solid proof-of-concept validation that inhibition of ALK is sufficient to attenuate the growth and prolif...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Abnormal expression of constitutively active anaplastic lymphoma kinase chimeric proteins (NPM-ALK) in the pathogenesis of anaplastic large-cell lymphoma (ALCL) is well defined. Recently, small molecule inhibitors have been reported that provide solid proof-of-concept validation that inhibition of ALK is sufficient to attenuate the growth and proli...

KDR kinase inhibition is considered to play an important role in regulating angiogenesis, which is vital for the survival and proliferation of tumor cells. Recently we disclosed a structure-based kinase inhibitor design strategy which led to the identification of a new class of VEGFR-2/KDR kinase inhibitors bearing heterocyclic substituted pyrazolo...

The modern drug discovery process is steadily becoming more information driven. Structural, physicochemical and ADME-Tox property profiles of reference (successful) ligands, along with structural information of their target proteins, have been extremely useful for early-stage drug discovery. Recently, databases of known biologically active ligands...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Methods for the calculation of two properties of interest in drug design, namely free energy of aqueous solvation and lipophilicity (log P), using fragmental methods are reviewed here. Though aqueous solvation free energies are commonly estimated using `whole molecule' methods such as GB/SA and AMSOL, we have recently shown that fragmental approach...

Solvation free energy is an important molecular characteristic useful in drug discovery because it represents the desolvation cost of a ligand binding to a receptor. Most of the recent developments in the estimation of solvation free energy require the use of molecular mechanics and dynamics calculations. Group contribution methods have been rarely...

The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of organic synthesis and biochemical screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compounds in the thousands. With automate...

Impressive advances in the fields of combinatorial chemistry and high-throughput screening have created a strong demand for computational methods for designing combinatorial libraries. Several computational and database tools aid in the design of such libraries. These include tools for reaction planning, scaffold selection, reagent searching, reage...

Molecular hydrophobicity (lipophilicity), usually quantified as log P (the logarithm of 1-octanol/water partition coefficient), is an important molecular characteristic in drug discovery. ALOGP and CLOGP are two of the most widely used methods for the estimation of log P. This work describes an extensive reparametrization of the atomic log P values...

In this study, structure-based drug design of matrix metalloproteinase inhibitors [human fibroblast collagenase (HFC), human fibroblast stromelysin (HFS), and human neutrophil collagenase (HNC)] was utilized in the development of potent hydroxamates which contain novel, heteroatom-based modifications of the P1' group. A series containing a P1' buty...

The pharmacophoric geometry for the inhibition of human fibroblast collagenase has been determined using a novel computational method. The inhibitors used in this study, which had from seven to 11 rotatable torsion angles, did not show any irreversible movement from the pharmacophore geometry during a 20 ps room temperature molecular dynamics simul...

Structure-based drug design (SBDD) and traditional SAR have guided the development of potent and selective hydroxamate inhibitors which contain heteroatom-based modifications of the P1′ group. These inhibitors may help delineate the in vivo roles of specific MMPs in normal and disease states.

Potent mechanism based inhibition of human leukocyte elastase (HLE) by tetrahydrobenzisothiazolones (bd2) is described. Structure activity relationships studies led to the identification of WIN 62816 (bd2c), the most potent inhibitor in this series with a K∗i = 0.7 nM.

Gelatinase B is potently inhibited by peptide hydroxamates, including molecules that have a R1′ group which is larger than the side chains of the natural amino acids.

Several methods are available in the literature for the conformational analysis of small molecules. Each of these methods has some advantages and some disadvantages. Also, each of these methods may be expected to perform better or worse on different types of molecules. There is no clear calibration of each of these methods against a “standardized”...

The comparative antileukemic activities of 21 novel nucleosides were determined in vitro by using cultured L1210 cells and analyzed for structure-related efficacy by a computer-aided receptor modeling method (REMOTEDISC) as recently described (Ghose, A. K.; et al. J. Med. Chem. 1989, 32, 746). The algorithm can be classified as a 3D-QSAR method and...

It has been shown earlier that atomic physicochemical properties can be extremely valuable in determining the molecular similarities and in modeling the hypothetical ligand-receptor interaction [Ghose . (1989) J. Med. Chem. 746 and references cited therein]. In all previous studies a discretized atom classification was used to assign the atomic oct...

The nucleoside transporter is an intrinsic membrane protein that mediates salvage of nucleosides from the extracellular medium. In this report, its binding sites have been characterized by a 3D-QSAR (three-dimensional structure-directed quantitative structure-activity relationships) receptor mapping technique. REMOTEDISC. The algorithm is applied t...

A novel computer-aided receptor modeling method, REMOTEDISC [J. Med. Chem. 32:746-756 (1989)], has been used to analyze the inhibition of labeled diazepam binding by 29 benzodiazepine receptor ligands. The method uses the three-dimensional structure, conformational energy, and important atom-based physicochemical properties to model the hypothetica...

The structural properties of the new antitumor agents 4-amino- (ARPP, 1a) and 4-methoxy-8-(β-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidines (MRPP, 1b) and the corresponding α-anomers 2a and 2b were studied by using molecular mechanics, molecular orbital (AM1) calculations, X-ray diffraction, and 1H NMR spectral data. In the 1H NMR spectra of 1a an...

A rationale for the antitumor activity of 4-methoxy- and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido-[5,4-d]pyrimidine (beta-MRPP and beta-ARPP, respectively) was studied by a molecular modeling method. Although these nucleoside analogues are structurally different from adenosine, they act as substrates for adenosine kinase. The molecular modelin...

We have shown previously that atomic values for physicochemical properties are an important guide for correlating the observed biological activity of the ligands to their chemical structure (Ghose, A. K.; Pritchett, A.; Crippen, G. M. J. Comput. Chem. 1988, 9, 80-90, and references cited therein). The objective of the present work is to (i) report...

The in vitro antiviral activity of 28 nucleosides against the parainfluenza virus type 3 has been analyzed by using a novel computer aided receptor modeling procedure. The method involves an extensive modification of our earlier work (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1985, 28, 333). It presents a more straightforward algorithm for the ste...

In an earlier article 8 the need was demonstrated for atomic physicochemical properties for three dimensional structure directed quantitative structure-activity relationships, and it was shown how atomic parameters can be developed for successfully evaluating the molecular octanol-water partition coefficient, which is a measure of hydrophobicity. I...

In an earlier paper (Ghose A. K.; Crippen, G. M. J. Comput. Chem. 1986, 7, 565) the need of atomic physicochemical properties for three-dimensional-structure-directed quantitative structure-activity relationships was demonstrated, and it was shown how atomic parameters can be developed to successfully evaluate the molecular water-1-octanol partitio...

Earlier we showed (A. K. Ghose and G. M. Crippen, J. Med. Chem. , 28, 333, 1985) the necessity of atomic physicochemical parameters in three-dimensional receptor mapping. Here we derive more refined and widely applicable hydrophobicity parameters. Carbon, hydrogen, oxygen, nitrogen, sulfur, and halogens are classified into 110 atom types. Among the...

A very efficient algorithm for determining the geometrically feasible binding modes of a flexible ligand molecule at the receptor site is presented. It is based on distance geometry but maintains the requirements of three dimensions. The distance geometry manipulation can superimpose two bodies without explicitly calculating the necessary rigid rot...

We present molecular orbital (CNDO/2) calculations on the key fragments of different dihydrofolate reductase inhibitors. Distance geometry analysis, physicochemical parameter dependent QSAR, and molecular shape analysis raised some questions regarding the basicity of the ring nitrogen (N1) in these inhibitors and the effect of the various substitue...

In earlier distance geometry related three-dimensional quantitative structure-activity relationships (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1984, 27, 901) the interactions of the ligand atom or group with the receptor site were evaluated empirically by using mathematical optimization techniques, without considering their physicochemical proper...

Insgesamt 62 Moleküle werden untersucht.

A common three-dimensional receptor model has been formulated for six different classes of rat liver dihydrofolate reductase inhibits using the distance geometry approach. Altogether, 62 molecules of five different classes were used to generate the receptor model, which has 11 attractive site points and 5 repulsive ones. It gave a fit having a corr...

Guided by the success of distance geometry in explaining the inhibition of dihydrofolate reductase by 68 quinazolines, we have made a combined analysis on the inhibition of rat liver dihydrofolate reductase by 33 triazines and 15 quinazolines. The model gave a fit having the correlation coefficient 0.892 and root mean square (rms) deviation 0.596 i...

Chinazolinderivate (I) werden unter Verwendung verbesserter Computer-Algorithmen als Dihydrofolatreduktase-Inhibitoren untersucht.

This is a reinvestigation of 68 quinazoline inhibitors of dehydrofolate reductase. As in the earlier study, the binding data fitted to an 11-point model of the site, but improved computer algorithms resulted in a much better overall fit (correlation coefficient 0.95, standard deviation 0.727 kcal) and a more accurate fit for some very loosely bound...

Ausgehend von den Malonaten (I) und (II) werden nach angegebenem Schema die Glutarimide (IX) synthetisiert (Ausb.-Angaben der Zwischenstufen in g).

Die Titelverbindungen (VII) bzw. (XI) wurden ausgehend von (I) bzw. (VIII) dargestellt, um den Einflu? von Substituenten am Benzolring auf die antineoglastische Aktivit?t dieser Verbindungen festzustellen.