Medicinal Chemistry Strategies Research Articles

Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib

Although orphan drug applications required by the EMEA must include assessments of similarity to pre-existing products, these can be difficult to quantify. Here we illustrate a paradigm in comparing nilotinib to the prototype kinase inhibitor imatinib, and equate the degree of structural similarity to differences in properties. Nilotinib was discovered following re-engineering of imatinib, employing structural biology and medicinal chemistry strategies to optimise cellular potency and selectivity towards BCR-ABL1. Through evolving only to conserve these properties, this resulted in significant structural differences between nilotinib and imatinib, quantified by a Daylight-fingerprint—Tanimoto similarity coefficient of 0.6, with the meaning of this absolute measure being supported by an analysis of similarity distributions of similar drug-like molecules. This dissimilarity is reflected in the drugs having substantially different preclinical pharmacology and a lack of cross-intolerance in CML patients, which translates into nilotinib being an efficacious treatment for CML, with a favourable side-effect profile.

Design, synthesis and qualitative structure–activity evaluations of novel hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and tetrahydropyrano[3,2-b]pyrrol-2(1H)-one derivatives as anticancer agents

Polysubstituted hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one and tetrahydropyrano[3,2-b]pyrrol-2(1H)-one derivatives were synthesized and biologically evaluated as novel anticancer agents. These motifs were produced by five steps reaction sequence in which Achmatowicz oxidative cyclization, is the basic protocol for such synthesis. To understand the structure–activity relationships of the newly synthesized motifs, two traditional medicinal chemistry strategies namely, ring expansion and contraction, were followed in this article. These studies indicated that tetrahydropyrano[3,2-b]pyrrol-2(1H)-one derivatives are more selective for breast cancer cell line compared to other cell lines under investigations. Furthermore, it was found that hexahydropyrano[3,2-c][1,2]diazepin-3(4H)-one derivatives are potent anticancer agents compared to tetrahydropyrano[3,2-b]pyrrol-2(1H)-one analogs. These findings, however, form the foundation for further investigation in our continuing efforts to develop selective anticancer agents.

Assessing the drug-likeness of lamellarins, a marine-derived natural product class with diverse oncological activities

Natural products currently represent an underutilized source of leads for the pharmaceutical industry, especially when one considers that almost 50% of all drugs were either derived from such sources or are very closely related. Lamellarins are a class of natural products with diverse biological activities and have entered into preclinical development for the treatment of multidrug-resistant tumors. Although these compounds demonstrated good cell penetration, as observed by their low μM activity in whole cell models, they have not been extensively profiled from a physicochemical point of view, and this is the goal of this study. For this study, we have determined the experimental logP values of a set of 25 lamellarins, given it is the single most important parameter in determining multiple ADMET parameters. We also discuss the relationship between this natural product class, natural product derivatives in development and on the market, oral marketed drugs, as well as drug molecules in development, using a range of physicochemical parameters in conjunction with principal components analysis (PCA). The impact of this systematic analysis on our ongoing medicinal chemistry strategy is also discussed.

Abstract PR-2: Discovery of p21-activated kinase inhibitor PF-03758309

Abstract The p21-activated kinase (PAK) family members are key effectors of Rho family GTPases, which act as regulatory switches that control such cellular processes as motility, proliferation, and cell survival. Some members of this family (such as Cdc42) have been shown to be required for Ras driven tumorigenesis. PAK4 is a key effector for Cdc42 and mediates downstream signals that control cell motility, proliferation and cell survival. The PAK family consists of PAK1,2,3 (‘group 1’) and PAK4,5,6 (‘group 2’). Both PAK4 and PAK1 have been shown to be required for Ras driven transformation. PAK4 has been shown to be oncogenic and able to drive anchorage independent growth when activated. PAK4 expression and activity is broadly up-regulated in solid tumors such as colon, ovarian and pancreatic cancers. Pfizer's PAK4 inhibitor program started with HTS of kinase focus library compounds. Multiple series were identified from the screening effort. Initial optimization mainly focused on kinase selectivity, ADME properties and ability to modulate target in vivo, leading to selection of pyrrolopyrazoles as the lead series. By hybridizing the pyrrolopyrazole core with aminopyrimidine series, we discovered potent PAK4 inhibitors with low to sub nM cellular activity. For the new hybrid series, the challenge was to attain good oral bioavailability. The observed poor absorption was likely due to high efflux nature of the template. Medicinal chemistry strategies, such as reducing molecular charge, lowering polar surface area and improving ligand efficiency, were applied to reduce efflux. As a result, two sub-series achieved excellent in vivo tumor growth inhibition when dosed orally. PF-03758309 has demonstrated excellent profile, leading to its selection as a clinical development candidate. PF-3758309 is a potent ATP-competitive inhibitor of PAK4 kinase domain (Kd = 4.5 nM). In engineered cell assays, PF-3758309 inhibited PAK4 dependent phosphorylation of its substrate GEF-H1 (IC50 = 1 nM). It potently inhibits the anchorage independent growth of HCT116 cells (IC50 = 0.24 nM). PF-3758309 exhibited broad anti-proliferative activity across a panel of 67 cell lines (CRC/pancreatic/NSCLC): 66% IC50 < 100 nM and 36% IC50 < 10 nM. In a human xenograft tumor model, PF-3758309 demonstrated a dose-dependent inhibition of both GEF-H1 and PAK4 phosphorylation. PF-3758309 is highly efficacious in human xenograft tumor models. Five of seven models tested showed robust tumor growth inhibition (>70%TGI at 15–20 mg/kg PO) by PF-3758309: HCT116, A549, MDAMB231, M24met, and Colo205. Broad kinase screening has demonstrated that this is a selective pan-PAK inhibitor with potential additional activities (e.g. AMPK). The pharmacodynamic and antitumor effects of PF-3758309 support its evaluation as an anticancer agent. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PR-2.

Abstract A86: Design, synthesis, and SAR of focal adhesion kinase (FAK) inhibitors

Abstract Focal adhesion kinase (FAK) is a non-tyrosine kinase that localizes to focal adhesion plaques. It is activated in response to intergin binding to cellular ligands and when phosphorylated inhibits anoikis allowing for anchorage independent cell growth. Recent studies have shown increased FAK expression and phosphorylation status in many types of invasive and aggressive human tumors strongly suggesting FAK is a possible target for anticancer chemotherapy. Literature, in house HTS and de novo studies identified 2, 4-diaminopyrimidines as potent FAK inhibitors. Early SAR efforts quickly determined that smaller substituents, particularly CF3, were optimal in the C5 position. Parallel medicinal chemistry strategies were executed for the C2 and C4 positions. These studies suggested that substituted aryl and fused heteroaryl groups at the C2 position in conjunction with substituted phenyl and heterocycles at the C4 position imparted optimum activity and metabolic stability. Inhibitor-FAK co-crystal structures were utilized to guide in the SAR strategy around the 2, 4-diaminopyrimidine template which afforded several lead compounds. The team's effort culminated in the advancement of PF-562,271 as a potent and reversible inhibitor of FAK (kinase IC50 of 2 nM and cell IC50 of 5 nM) that is > 100x selective against a long list of non-target kinases. In summary, detailed SAR studies were executed on the 2, 4-diaminopyrimidine templates that produced potent inhibitors of FAK with improved ADME properties, and identified a novel and potent series of FAK inhibitors that are selective against most other kinases and have shown activity in clinical trials. This poster will present design, synthesis, challenging chemistry, optimization, and complete inhibitor chemical structures of lead analogs. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A86.

Design Strategies of Novel NNRTIs to Overcome Drug Resistance

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). However, to a great extent, the efficacy of NNRTI drugs is impaired by rapid emergence of drug-resistance mutations. Fortunately, detailed analysis of a wide range of crystal structures of HIV-1 RT/NNRTI complexes together with data on drug resistance mutations has identified factors important for design of inhibitors and resilience to mutations, such as, exhibiting conformational flexibility and positional adaptability of NNRTIs, forming extensive main chain hydrogen bonding, targeting highly conserved residues in HIV-1 RT and possessing unconventional mechanisms for NNRTI-mediated inhibition of RT. Besides, the plasticity of NNRTIs binding pocket (NNIBP) also provides a broad space for the discovery of new generations of NNRTIs. For instance, the composite binding pocket, integrated all available crystal structure information about the NNRTI binding site of HIV RT, was demonstrated to be an effective tool to better understand the flexible nature of the binding pocket and to identify specific inhibitors. The RT/solvent interface proved to be an attractive site for incorporating a moiety to improve water solubility and pharmacokinetics or introducing a second pharmacophore to construct multifunctional ligand. Totally, the characterization of NNRTIs and NNIBP may help in the design of more effective drugs that are potent toward wild type and drug-resistant strains of RT. In this paper we attempt to translate the general knowledge gained from a large number of related literature into a set of medicinal chemistry strategies to improve the drug resistance profile of NNRTIs.

Simultaneous Optimization of Potency, Selectivity and Physicochemical Properties for Cannabinoid CB2 Ligands

Non-selective cannabinoid ligands display a wide range of physiological effects including analgesic, anti-inflammatory, anti-convulsive and immuno-suppressive activities. A separation between therapeutic effects and undesirable CNS side effects may be accomplished by increasing the selectivity for the CB(2) receptor over the CB(1) receptor. There is considerable interest in developing new cannabimimetic compounds possessing preferentially high affinity for the CB(2) receptor as potential novel therapeutics for the treatment of inflammation and chronic pain. This review will summarize the literature on selective cannabinoid CB(2) receptor agonists from 2007 to the present, with special emphasis on SAR and medicinal chemistry strategies to improve physicochemical properties, metabolic stability and oral bioavailabilty of these inherently lipophilic ligands. Incorporating physicochemical property filters early in hit identification, concurrent screening of liver microsomal stability and addressing metabolic hot-spots through structural modifications or bio-isosteric replacements during lead optimization led to a number of structurally diverse CB(2) agonists with good oral bioavailability and in vivo efficacy in rodent models of pain.

Synthesis and SAR studies of 1,4-diazabicyclo[3.2.2]nonane phenyl carbamates – subtype selective, high affinity α7 nicotinic acetylcholine receptor agonists

The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of α7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity α7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.

Medicinal chemistry strategies in follow-on drug discovery

Drug discovery targeting novel mechanisms has become extremely expensive and risky. The annual first-in-class drug approvals have not been satisfactory in the past decade (two to six per year) despite an increased R&D budget. Follow-on programs targeting proven mechanisms are less risky and costly but can produce drugs with meaningful differentiations and thus can play an important supporting role. This article will discuss the medicinal chemistry strategies that have been utilized by the pharmaceutical industry to exploit validated therapeutic targets.

The design and discovery of novel amide CCR5 antagonists

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR’s which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.

Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels

Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies for discovering new classes of antagonist for trans-membrane ion channels have been limited to mostly broad screening compound arrays. We have developed new sodium channel antagonist based on a propofol scaffold using the ligand based strategy of comparative molecular field analysis (CoMFA). The resulting CoMFA model was correlated and validated to provide insights into the design of new antagonists and to prioritize synthesis of these new structural analogs (compounds 4 and 5) that satisfied the steric and electrostatic model. Compounds 4 and 5 were evaluated for [ 3H]-batrachotoxinin-A-20-α-benzoate ([ 3H]-BTX-B) displacement yielding IC 50’s of 22 and 5.7 μM, respectively. We further examined the potency of these two compounds to inhibit neuronal sodium currents recorded from cultured hippocampal neurons. At a concentration of 50 μM, compounds 4 and 5 tonically inhibited sodium channels currents by 59 ± 7.8% ( n = 5) and 70 ± 7.5% ( n = 7), respectively. This clearly demonstrates that these compounds functionally antagonize native neuronal sodium channel currents. In summary, we have shown that CoMFA can be effectively used to discover new classes of sodium channel antagonists.

Editorial [Hot topic: Medicinal Chemistry Strategies to Minimize hERG Channel Effects 23 May (Guest Editor:Mark T. Bilodeau)

Editorial [Hot topic: Medicinal Chemistry Strategies to Minimize hERG Channel Effects 23 May (Guest Editor:Mark T. Bilodeau)

The Discovery of Taranabant, a Selective Cannabinoid‐1 Receptor Inverse Agonist for the Treatment of Obesity

The cannabinoid-1 receptor (CB1R) has emerged as one of the most important targets for the treatment of obesity. Pioneering studies with rimonabant helped to validate animal models of food intake reduction and weight loss and made the connection to weight loss in the clinic. A novel, acyclic amide was identified from a high throughput screen (HTS) of the Merck sample collection and found to be a potent and selective CB1R inhibitor. Further optimization led to more potent compounds that were orally active in reducing food intake and weight loss in diet-induced obese (DIO) rats. However, many of these analogues exhibited a high potential for bioactivation and the formation of reactive intermediates and covalent protein binding. Identification of the products of oxidative metabolism guided medicinal chemistry efforts to minimize the formation of these unwanted products. These efforts resulted in the identification of the CB1R inverse agonist, taranabant, which is currently in Phase-III clinical studies for the treatment of obesity. This mini-review will describe some of the medicinal chemistry strategies that were followed from the original high throughput screen hit to the discovery of taranabant.

Leukotrienes, Antileukotrienes and Asthma

Leukotrienes (LTs), including LTB(4) and cysteinyl-LTs (CysLTs) (LTC(4), LTD(4), and LTE(4)), are potent inflammatory lipid mediators which are derived from 5-lipoxygenase activity. CysLTs, which stimulate CysLT(1) and CysLT(2) receptor subtypes, are functionally involved in the pathophysiology of asthma. Selective CysLT(1) receptor antagonists are effective anti-asthmatic drugs. CysLT(1) receptor antagonists have been developed from leukotriene structural analogs, analogs of FPL 55712, a chromone carboxylic acid, and by random screening of corporate compound banks. This review will examine the biosynthesis, metabolism and mechanism of action of leukotrienes, their role in asthma, the therapeutic implications of the leukotriene pathway inhibition for asthma, and the medicinal chemistry strategies that have been exploited in the design of potent and selective CysLT(1) receptor antagonists.

Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives

The observed antiobesity effect of rimonabant (1) in a pharmacological rodent model 10 years ago has led to a surge in the search for novel cannabinoid CB1 antagonists as a new therapeutic target for the treatment of obesity. Rimonabant showed clinical efficacy in the treatment of obesity and also improved cardiovascular and metabolic risk factors. Cannabinoid CB1 receptor antagonists have also good prospects in other therapeutic areas, including smoking and alcohol addiction as well as cognitive impairment. Solvay's research achievements in this fast-moving field are reported in relation with the current state of the art. Several medicinal chemistry strategies have been pursued. The application of the concept of conformational constraint led to the discovery of more rigid analogs of the prototypic CB1 receptor antagonist rimonabant. Replacement of the central heterocyclic pyrazole ring in rimonabant yielded imidazoles, triazoles, and thiazoles as selective CB1 receptor antagonists. Dedicated medium-throughput screening efforts delivered one 3,4-diarylpyrazoline hit. Its poor pharmacokinetic properties were successfully optimized which led to the discovery of orally active and highly CB1/CB2 receptor selective analogs in this series. Regioisomeric 1,5-diarylpyrazolines, 1,2-diarylimidazolines, and water-soluble imidazoles have been designed as novel CB1 receptor antagonist structure classes.

Design, Structure Activity Relationships and X-Ray Co-Crystallography of Non-Steroidal LXR Agonists

The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as a heterodimer with the Retinoid X Receptor (RXR). Upon agonist binding, the formation of the LXR/RXR heterodimer takes place and ultimately the regulation of a number of genes begins. The LXR isoforms share 77% sequence homology, with LXRalpha having highest expression in liver, intestine, adipose tissue, and macrophages and LXRbeta being ubiquitously expressed. The aim of this article is to review the reported medicinal chemistry strategies towards the optimisation of novel non-steroidal chemotypes as LXR agonists. An analysis of the structural features important for LXR ligand binding will be given, utilising both structural activity relationship data obtained from LXR assays as well as X-ray co-crystallographic data obtained with LXR ligands and the LXR ligand binding domain (LBD). The X-ray co-crystallographic data analysis will detail the key structural interactions required for LXR binding/agonist activity and reveal the differences observed between chemotype classes. It has been postulated that a LXRbeta selective compound may have a beneficial outcome on the lipid profile for a ligand by dissociating the favourable and unfavourable effects of LXR agonists. Whilst there have been a few examples of compounds showing a modest level of LXRalpha selectivity, obtaining a potent LXRbeta selective compound has been more challenging. Analysis of the SAR and X-ray co-crystallographic data suggests that the rational design of a LXRbeta selective compound will not be trivial.

Synthesis, Crystal Structure, and Activity of Pyrazole-Based Inhibitors of p38 Kinase

A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.

Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping

Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3β was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.

Novel Selective Inhibitors of Neutral Endopeptidase for the Treatment of Female Sexual Arousal Disorder. Synthesis and Activity of Functionalized Glutaramides

Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)

European Medicinal Chemistry—Strategies, Targets, and Drugs under the Spotlight

ChemMedChemVolume 1, Issue 1 p. 155-157 Conference Report European Medicinal Chemistry—Strategies, Targets, and Drugs under the Spotlight Jörg Cramer Dr., Jörg Cramer Dr. joerg.cramer@intervet.com Intervet Innovation GmbH, Zur Propstei, 55270 Schwabenheim, Germany, Fax: (+49) 6130-948-517Search for more papers by this authorMichael Berger Dr., Michael Berger Dr. Intervet Innovation GmbH, Zur Propstei, 55270 Schwabenheim, Germany, Fax: (+49) 6130-948-517Search for more papers by this author Jörg Cramer Dr., Jörg Cramer Dr. joerg.cramer@intervet.com Intervet Innovation GmbH, Zur Propstei, 55270 Schwabenheim, Germany, Fax: (+49) 6130-948-517Search for more papers by this authorMichael Berger Dr., Michael Berger Dr. Intervet Innovation GmbH, Zur Propstei, 55270 Schwabenheim, Germany, Fax: (+49) 6130-948-517Search for more papers by this author First published: 05 January 2006 https://doi.org/10.1002/cmdc.200500049Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume1, Issue1January 16, 2006Pages 155-157 RelatedInformation