TRPV1 antagonism by piperazinyl-aryl compounds: A Topomer-CoMFA study and its use in virtual screening for identification of novel antagonists.

Transient Receptor Potential Vanilloid, member 1 (TRPV1), is a non-selective cation channel belonging to the transient receptor potential (TRP) family of ion channels. It occurs in the peripheral and central nervous system, activated by a variety of exogenous and endogenous stimuli, thus playing a key role in transmission of pain. This has been a target for chronic pain since more than a decade and a number of antagonists that progressed into clinical trials have failed due to the unexpected side effect of core body temperature rise, thus halting progress in this field.

A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease.

Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule.

Focal adhesion kinase inhibitors in the treatment of metastatic cancer: a patent review.

Introduction: Focal adhesion kinase (FAK) plays a prominent role in integrin signaling. FAK activation increases phosphorylation of Tyr397 and other sites of the protein. FAK-dependent activation of signaling pathways implicated in controlling essential cellular functions including growth, proliferation, survival and migration.

Pyrid-2-yl and 2-CyanoPhenyl fused heterocyclic compounds as human P2X3 inhibitors: a combined approach based on homology modelling, docking and QSAR analysis.

P2X receptors are hetero-oligomeric proteins that function as membrane ion channels and are gated by extracellular ATP. The hP2X[Formula: see text] subunit is a constituent of the channels on a subset of sensory neurons involved in pain signaling, where ATP released by damaged and inflamed tissue can initiate action potentials. Hence, the inhibition of ATP-activated P2X3 receptor is an exciting approach for the treatment of inflammatory and neuropathic pain.

A neural network-based QSAR approach for exploration of diverse multi-tyrosine kinase inhibitors and its comparison with a fragment- based approach.

Receptor and non-receptor tyrosine kinases have emerged as clinically useful drug target for treating certain types of cancer. It is well known that tyrosine kinase inhibitors with multi-kinases inhibitory potency are useful in anticancer therapy. In recent study, we have demonstrated application of a novel Group based QSAR (GQSAR) method to assist in lead optimization of multi-tyrosine kinase (PDGFR-beta, FGFR-1 and SRC) inhibitors.

Small molecule inhibitors of PIM1 kinase: July 2009 to February 2013 patent update.

Introduction: The proviral insertion in murine (PIM) lymphoma proteins for which three isoforms, PIM1, PIM2 and PIM3 have been identified, belonging to the family of serine/threonine kinases has emerged recently as an important therapeutic target for the development of selective inhibitors as the new drugs for treating hematological malignancies and solid tumors. The small molecules developed by academia and the pharmaceutical industry have steadily increased in the last few years. Several drug discovery groups focus on treating disorders, such as cancer mediated by PIM kinase, have provided preclinical evidence suggesting that PIM inhibitor provides anti-apoptotic activity, inhibit cell survival and cell proliferation.

Could MM-GBSA be accurate enough for calculation of absolute protein/ligand binding free energies?

Implicit solvation methods such as MM-GBSA, when applied to evaluating protein/ligand binding free energies, are widely believed to be accurate only for the estimation of relative binding free energies for a congeneric series of ligands. In this work, we show that the MM-GBSA flavor of Prime 3.0, VSGB-2.

3D-QSAR analysis of TRPV1 inhibitors reveals a pharmacophore applicable to diverse scaffolds and clinical candidates.

TRPV1 (Transient Receptor Potential Vanilloid Type 1) receptor, a member of Transient Receptor Potential Vanilloid subfamily of ion channels, occurs in the peripheral and central nervous system, and plays a key role in transmission of pain. Consequently, this has been the target for discovery of several pain relieving agents which have undergone clinical trials. Though several TRPV1 antagonists have progressed to become clinical candidates, many are known to cause temperature elevation in humans, halting their further advancement, and signifying the need for new chemotypes.

Applying conformational selection theory to improve crossdocking efficiency in 3-phosphoinositide dependent protein kinase-1.

The emerging picture of biomolecular recognition is that of conformational selection followed by induced-fit. Conformational selection theory states that binding partners exist in various conformations in solution, with binding involving a "selection" between complementary conformers. In this study, we devise a docking protocol that mimics conformational selection in protein-ligand binding and demonstrate that it significantly enhances crossdocking accuracy over Glide's flexible docking protocol, which is widely used in the pharmaceutical industry.

Toward a general predictive QSAR model for gamma-secretase inhibitors.

Gamma secretase (GS) is an appealing drug target for Alzheimer disease and cancer because of its central role in the processing of amyloid precursor protein and the notch family of proteins. In the absence of three-dimensional structure of GS, there is an urgent need for new methods for the prediction and screening of GS inhibitors, for facilitating discovery of novel GS inhibitors. The present study reports QSAR studies on diverse chemical classes comprising 233 compounds collected from the ChEMBL database.

Atom type preferences, structural diversity, and property profiles of known drugs, leads, and nondrugs: a comparative assessment.

A new characterization of known drug, lead, and representative nondrug databases was performed taking into account several properties at the atomic and molecular levels. This characterization included atom type preferences, intrinsic structural diversity (Atom Type Diversity, ATD), and other well-known physicochemical properties, as an approach for rapid assessment of druglikeness for small molecule libraries. To characterize ATD, an elaborate united atom classification, UALOGP (United Atom Log P), with 148 atom types, was developed along with associated atomic physicochemical parameters.

Dipeptidyl-quinolone derivatives inhibit hypoxia inducible factor-1α prolyl hydroxylases-1, -2, and -3 with altered selectivity.

Intracellular levels of the hypoxia-inducible transcription factor (HIF) are regulated under normoxic conditions by prolyl hydroxylases (PHD1, 2, and 3). Treatment of cells with PHD inhibitors stabilizes HIF-1α, eliciting an artificial hypoxic response that includes the transcription of genes involved in erythropoiesis, angiogenesis, and glycolysis. The different in vivo roles of the three PHD isoforms are not yet known, making a PHD-selective inhibitor useful as a biological tool.

2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics.

A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis.

Structure-guided design of substituted aza-benzimidazoles as potent hypoxia inducible factor-1alpha prolyl hydroxylase-2 inhibitors.

We report the structure-based design and synthesis of a novel series of aza-benzimidazoles as PHD2 inhibitors. These efforts resulted in compound 22, which displayed highly potent inhibition of PHD2 function in vitro.

Discovery of dihydroquinoxalinone acetamides containing bicyclic amines as potent Bradykinin B1 receptor antagonists.

Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC(50)s<0.2 nM in a human B1 receptor functional assay.

Discovery of novel hydroxy-thiazoles as HIF-alpha prolyl hydroxylase inhibitors: SAR, synthesis, and modeling evaluation.

Inhibition of the PHD2 enzyme has been associated with increased red blood cell levels. From a screening hit, a series of novel hydroxyl-thiazoles were developed as potent PHD2 inhibitors.

Three-dimensional quantitative structure-activity relationships and activity predictions of human TRPV1 channel antagonists: comparative molecular field analysis and comparative molecular similarity index analysis of cinnamides.

3D-QSAR models for human TRPV1 channel antagonists were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), using a training set of 61 cinnamide TRPV1 antagonists and tested on an independent test set of 47 antagonists. Molecular alignment procedure included weights for both internal energy and atom-to-atom matching against a reference or probe. Sensitivity of results on partial charge assignments was explored using multiple charge sets.

Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors.

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin-2(1H)-ones as CDK5 inhibitors.

Novel vanilloid receptor-1 antagonists: 1. Conformationally restricted analogues of trans-cinnamides.

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead.

Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity.

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.

Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents.

We report the discovery of potent agonists for the human formyl-peptide-like 1 receptor (hFPRL1). These compounds did not act at a closely related receptor denoted human formyl peptide receptor (hFPR) up to 10 microM concentration. Recent studies have indicated that agonizing this receptor may promote resolution of inflammation.

Molecular determinants of vanilloid sensitivity in TRPV1.

Vanilloid receptor 1 (TRPV1), a membrane-associated cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by physical stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [(3)H]RTX binding in membranes prepared from their dorsal root ganglia.

(4-Piperidinylphenyl)aminoethyl amides as a novel class of non-covalent cathepsin K inhibitors.

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays.

Knowledge-based approaches in the design and selection of compound libraries for drug discovery.

In the past decade, the pharmaceutical industry has realized the increasing significance of impacting the early phase hit-to-lead development in the drug discovery process. In particular, knowledge-based approaches emerged and evolved to address a multitude of issues such as absorption, distribution, metabolism and excretion (ADME), potency, toxicity and overall drugability. Each of these approaches seeks to bring together all relevant pieces of information and create a knowledge-oriented process to deploy such information in drug discovery.