Prashant R. Murumkar

Current perspective of TACE inhibitors: A review

Rheumatoid Arthritis (RA) is one of the most common autoimmune inflammatory conditions, affecting approximately 1% of the adult population worldwide. TNF-alpha is a pleitropic, pro-inflammatory cytokine which plays a pivotal role in the origin and progression of RA and other immune mediated disorders. The success of anti-TNF-alpha biological agents proved that inhibition of TNF-alpha could result in effective control of RA. Since the discovery of anti-TNF-alpha biologicals, much efforts have gone into developing an orally bioavailable small size TNF-alpha antagonist. One of the ways to block TNF-alpha in biological fluids is to inhibit TNF-alpha converting enzyme (TACE). This target has been validated in preclinical trials using TACE inhibitors. But, even after more than a decade no single TACE inhibitor has passed the Phase II clinical trials. Very recently, it has been shown that TACE inhibitors could also be used for inhibition of pathogenic EGFR signaling in cancer. Hence, TACE inhibitors could perform a dual role, in curing not only RA but also certain cancerous conditions. Developments in the field have prompted us to review the research work on TACE inhibitors, especially their structure activity relationships and molecular modeling studies.

Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists—A perspective

Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT(1) and AT(2). Angiotensin II through AT(1) receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT(1)) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT(1) antagonists are based on modifications of losartan structure, the first clinically used AT(1) antagonist. In this review, a comprehensive presentation of the literature on AT(1) receptor antagonists has been given.

Prodrug Designing of NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs), commonly used for the treatment of chronic inflammatory diseases suffer from several undesired side effects, the most important being gastrointestinal (GI) irritation and ulceration. The prodrug designing is one of the several strategies used to overcome this drawback. The rationale behind the prodrug concept is to achieve temporary blockade of the free carboxylic group present in the NSAIDs till their systemic absorption. In this paper, a review on the concept of prodrugs designing of NSAIDs to improve their efficacy and reduce the toxicity is being presented.

Novel TACE inhibitors in drug discovery: a review of patented compounds.

TNF-α converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is believed to play pathophysiological roles in inflammation, anorexia, cachexia, septic shock, viral replication and so on. TNF-α is a key player in inflammation and joint damage in rheumatoid arthritis. While a variety of TACE inhibitors have been reported in the literature, a vast majority of these compounds are peptidic and peptide-like compounds that are expected to have bioavailability and pharmacokinetic problems, common to such compounds, limiting their clinical effectiveness. Low molecular mass, long acting, orally bioavailable inhibitors of TACE are, therefore, highly desirable for the treatment of potential chronic diseases mentioned above. A review of patented compounds as TACE inhibitors in drug discovery is given. A selection of interesting patents recorded from 2001 to 2009 is presented. Various novel TACE inhibitors developed by different companies have been discussed.

Development of predictive pharmacophore model for in silico screening, and 3D QSAR CoMFA and CoMSIA studies for lead optimization, for designing of potent tumor necrosis factor alpha converting enzyme inhibitors

A chemical feature-based pharmacophore model was developed for Tumor Necrosis Factor-α converting enzyme (TACE) inhibitors. A five point pharmacophore model having two hydrogen bond acceptors (A), one hydrogen bond donor (D) and two aromatic rings (R) with discrete geometries as pharmacophoric features was developed. The pharmacophore model so generated was then utilized for in silico screening of a database. The pharmacophore model so developed was validated by using four compounds having proven TACE inhibitory activity which were grafted into the database. These compounds mapped well onto the five listed pharmacophoric features. This validated pharmacophore model was also used for alignment of molecules in CoMFA and CoMSIA analysis. The contour maps of the CoMFA/CoMSIA models were utilized to provide structural insight for activity improvement of potential novel TACE inhibitors. The pharmacophore model so developed could be used for in silico screening of any commercial/in house database for identification of TACE inhibiting lead compounds, and the leads so identified could be optimized using the developed CoMSIA model. The present work highlights the tremendous potential of the two mutually complementary ligand-based drug designing techniques (i.e. pharmacophore mapping and 3D-QSAR analysis) using TACE inhibitors as prototype biologically active molecules.

Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists.

Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacokinetic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antagonists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review.

3D-Quantitative Structure–Activity Relationship Studies on Benzothiadiazepine Hydroxamates as Inhibitors of Tumor Necrosis Factor-α Converting Enzyme

A set of 29 benzothiadiazepine hydroxamates having selective tumor necrosis factor‐α converting enzyme inhibitory activity were used to compare the quality and predictive power of 3D‐quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices models for the atom‐based, centroid/atom‐based, data‐based, and docked conformer‐based alignment. Removal of two outliers from the initial training set of molecules improved the predictivity of models. Among the 3D‐quantitative structure–activity relationship models developed using the above four alignments, the database alignment provided the optimal predictive comparative molecular field analysis model for the training set with cross‐validated r2 (q2) = 0.510, non‐cross‐validated r2 = 0.972, standard error of estimates (s) = 0.098, and F = 215.44 and the optimal comparative molecular similarity indices model with cross‐validated r2 (q2) = 0.556, non‐cross‐validated r2 = 0.946, standard error of estimates (s) = 0.163, and F = 99.785. These models also showed the best test set prediction for six compounds with predictive r2 values of 0.460 and 0.535, respectively. The contour maps obtained from 3D‐quantitative structure–activity relationship studies were appraised for activity trends for the molecules analyzed. The comparative molecular similarity indices models exhibited good external predictivity as compared with that of comparative molecular field analysis models. The data generated from the present study helped us to further design and report some novel and potent tumor necrosis factor‐α converting enzyme inhibitors.

Development of Predictive 3D‐QSAR CoMFA and CoMSIA Models for β‐aminohydroxamic Acid‐Derived Tumor Necrosis Factor‐α Converting Enzyme Inhibitors

A three‐dimensional quantitative structure–activity relationship study was performed on a series of β‐aminohydroxamic acid‐derived tumor necrosis factor‐α converting enzyme inhibitors employing comparative molecular field analysis and comparative molecular similarity indices analysis techniques to investigate the structural requirements for the inhibitors, and derive a predictive model that could be used for the design of novel tumor necrosis factor‐α converting enzyme inhibitors. log P was used as an additional descriptor in the comparative molecular field analysis analysis to study the effects of lipophilic parameters on activity. Inclusion of log P did not improve the models significantly. The statistically significant model was established with 45 molecules, which were validated by a test set of 11 compounds. Ligand molecular superimposition on the template structure was performed by the atom‐/shape‐based root mean square fit and database alignment methods. Docked conformer based alignment (V) yielded the best predictive comparative molecular field analysis model  = 0.673,  = 0.860, F‐value = 86.073, predictive r 2 = 0.642, with two components, standard error of prediction = 0.394 and standard error of estimates = 0.243 while the comparative molecular similarity indices analysis model yielded  = 0.635,  = 0.858, F‐value = 84.451, predictive r 2 = 0.441 with three components, standard error of prediction = 0.393 and standard error of estimates = 0.245. The contour maps obtained from three‐dimensional quantitative structure–activity relationship studies were appraised for activity trends for the molecules analyzed. The comparative molecular field analysis models exhibited good external predictivity as compared with that of comparative molecular similarity indices analysis models. The model generated through comparative molecular field analysis was validated with the IK‐682. The data generated from this study may guide our efforts in designing and predicting the tumor necrosis factor‐α converting enzyme inhibitory activity of novel molecules.

Structural Investigations of Acridine Derivatives by CoMFA and CoMSIA Reveal Novel Insight into Their Structures toward DNA G-Quadruplex Mediated Telomerase Inhibition and Offer a Highly Predictive 3D-Model for Substituted Acridines

Stabilization of G-quadruplex structures formed from telomeric DNA, by means of G-quadruplex selective ligands, is a means of inhibiting the telomerase enzyme. This makes G-quadruplex an emerging target for cancer therapy. The objective of the current 3D QSAR study is to uncover structural requirements for acridine derivatives, which would eventually assist and complement the rational drug-design attempts. Various protonation strategies were investigated to check in situ protonation sites present on ligands when they bind to G-quadruplex, and predictive 3D-QSAR CoMFA and CoMSIA models have been developed. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were carried out on substituted acridines as telomerase inhibitors. Molecular models with good predictive power were derived using steric, electrostatic, hydrophobic, and H-bond donor fields of the compounds. The CoMSIA coefficient contour plots identified several key features explaining the wide range in activities. The present study not only offers a highly significant predictive CoMSIA model for trisubstituted acridine derivatives as telomerase inhibitors but also throws more light on the molecular structure of these compounds at physiological pH.

Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer’s Agents: Synthesis and Biological Evaluation

A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimers disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC50 value of 0.30 ± 0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aβ1-42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aβ1-42-induced toxicity by attenuating abnormal levels of Aβ1-42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects.