Discovery of Novel Aminotetralines and Aminochromanes as Selective and Competitive Glycine Transporter 1 (GlyT1) Inhibitors.

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7 S,8 R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7 S,8 R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7 S,8 R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.

De Novo Design, Synthesis, and Biological Evaluation of 3,4-Disubstituted Pyrrolidine Sulfonamides as Potent and Selective Glycine Transporter 1 Competitive Inhibitors.

The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities.

Small molecule library synthesis using segmented flow.

Flow chemistry has gained considerable recognition as a simple, efficient, and safe technology for the synthesis of many types of organic and inorganic molecules ranging in scope from large complex natural products to silicon nanoparticles. In this paper we describe a method that adapts flow chemistry to the synthesis of libraries of compounds using a fluorous immiscible solvent as a spacer between reactions. The methodology was validated in the synthesis of two small heterocycle containing libraries. The reactions were performed on a 0.2 mmol scale, enabling tens of milligrams of material to be generated in a single 200 mL reaction plug. The methodology allowed library synthesis in half the time of conventional microwave synthesis while maintaining similar yields. The ability to perform multiple, potentially unrelated reactions in a single run is ideal for making small quantities of many different compounds quickly and efficiently.

Scaffold oriented synthesis. Part 4: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing heterocycle forming and multicomponent reactions.

We report the synthesis and biological evaluation of 5-substituted indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing heterocycle forming and multicomponent reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for Gsk3ß, Rock2, and Egfr.

Scaffold oriented synthesis. Part 3: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing [2+3] cycloadditions.

We report the synthesis and biological evaluation of 5-substituted indazoles and amino indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing [2+3] cycloaddition reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for numerous kinases such as Rock2, Gsk3ß, Aurora2 and Jak2.

When analoging is not enough: scaffold discovery in medicinal chemistry.

IMPORTANCE OF THE FIELD: As an integral part of lead generation and optimization, scaffold discovery has broad implications in drug discovery. Currently available chemical scaffolds might be inadequate to provide drug-like ligands for new targets such as phosphatases and protein-protein interactions and therapeutically useful chemical space needs to be continuously explored. New scaffolds are often desired to overcome major hurdles (e.g., potency plateau, selectivity, pharmacokinetics, etc.) in lead generation and optimization. Timely discovery of proof-of-concept compounds facilitates target validation, diversifies clinical candidates and improves the overall success rate of drug discovery. AREAS COVERED IN THIS REVIEW: This analysis discusses the strategies involved in finding new scaffolds (i.e., fragment-, ligand- and structure-based design) and their applications (e.g., improve potency/selectivity, multiple ligand design, protein-protein interactions, etc.) in drug discovery. WHAT THE READER WILL GAIN: The readers will learn the strategies involved in scaffold design and the problems that they solve. They will also gain the understanding of the circumstances suitable for using scaffold design. TAKE HOME MESSAGE: Scaffold is defined by the authors as a biological target dependent concept. Therapeutically useful scaffolds are limited and the identification of new scaffolds is sometimes required to overcome major optimization hurdles. However, depending on the promiscuity of the binding pocket of the target and the validity of the optimization protocol, finding better scaffolds can be a challenging task. Several strategies in scaffold discovery have emerged or matured owing to recent trends such as pursuit of targets from new proteomic families, lack of validated targets, advances in synthesis and biological assays and adoption of in vitro activity-driven screening paradigms.

Kinase-targeted libraries: the design and synthesis of novel, potent, and selective kinase inhibitors.

Protein kinases continue to hold tremendous promise for therapeutic intervention, and the search for novel, safe and efficacious kinase inhibitors has intensified over the past decade. Given that most kinases are readily inhibited by organic small molecules and that a wealth of structural data exists on kinase-inhibitor complexes, there has been almost universal success in the design and identification of potent kinase inhibitors. The issues of non-selectivity and congested IP space, however, present formidable challenges for the successful clinical development of these compounds. We describe a systematic approach implemented at Abbott to enable the rapid discovery and design of novel and potent kinase inhibitors that provide additional opportunities for targeting new intellectual property space and achieving acceptable selectivity profiles.

Scaffold oriented synthesis. Part 2: Design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors.

We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).

Isocyanide-based multicomponent reactions in drug discovery.

This review describes recent advances in the application of isocyanide-based multicomponent reactions (IMCRs) in drug discovery and summarizes the various chemotypes used to probe biological targets. In the past couple of years, IMCR-derived ligands have been used to develop agents against infectious diseases and to interfere with protein-protein interactions. Additionally, they were active against a variety of targets such as enzymes, GPCRs and ion channels. The rational for the chemical biologist to apply such diversity generating chemistries is also discussed.

Concise construction of novel bridged bicyclic lactams by sequenced Ugi/RCM/Heck reactions.

Herein we report a concise protocol for the diastereoselective synthesis of novel bridged bicyclic lactams from commercially available components by the sequence of Ugi, ring-closing metathesis (RCM), and Heck reactions. X-ray diffraction studies revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom.

Topography-biased compound library design: the shape of things to come?

The design and synthesis of quality compound libraries is of critical importance to any pharmaceutical company that relies on high throughput screening efforts for the identification of lead compounds. In this perspective, we use a moment of inertia derived shape analysis to interrogate potential libraries for chemical synthesis. An analysis of known 'Rule of Five' compliant drug shapes using this methodology clearly highlights compound libraries that may be reasonably expected, shape wise, to interact with biologically relevant protein active site topography and those that, although being structurally diverse in shape, have little chance of being pharmacologically productive. The use of multicomponent reactions as a means of producing structurally novel, bioactive compounds in a synthetically expeditious manner is also highlighted.

1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel.

The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.

Synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted receptor tyrosine kinase inhibitors.

We report the synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted kinase inhibitors. Initial efforts focused on the development of selective KDR inhibitors, while later strategies involved the improvement of potency toward multiple kinase targets. Thus, several compounds were identified as potent KDR, Flt1, Flt3, and c-Kit inhibitors.

Synthesis of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by sequential Ugi/[2+2] ene-enone photocycloadditions.

[structure: see text]. We report a new methodology for the construction of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by combining the Ugi multicomponent reaction with [2+2] enone-olefin photochemical transformations. The overall sequence is capable of creating up to five stereocenters; however, in most cases, only two diastereomers are observed.

The identification of new protein kinase inhibitors as targets in modern drug discovery.

In recent years there has been great interest in developing protein kinase inhibitors as therapeutic agents for a variety of diseases. This article provides an overview on the history, development and validity of kinases as drug targets, as well as a description of kinase research, including its limitations, challenges and successes.

1,4-Dihydroindeno[1,2-c]pyrazoles as novel multitargeted receptor tyrosine kinase inhibitors.

A series of 1,4-dihydroindeno[1,2-c]pyrazoles with a 3-thiophene substituent carrying a urea-type side chain were identified as potent multitargeted (VEGFR and PDGFR families) receptor tyrosine kinase inhibitors. A KDR homology model suggested that the urea moiety is able to interact with a recognition motif in the hydrophobic specificity pocket of the enzyme.

Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors.

A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.

The use of three-dimensional shape and electrostatic similarity searching in the identification of a melanin-concentrating hormone receptor 1 antagonist.

To aid in the identification of novel melanin-concentrating hormone receptor 1 (MCHr1) antagonists, a unique virtual library of readily synthesized molecules was designed and assembled based on 323 monomer compounds containing reactive moieties in combination with 30 core molecules having diamine functionality. The resulting library of 3,129,870 molecules was searched using three-dimensional shape similarity measures that were complimented with a novel electrostatic distribution similarity-matching algorithm. One of the top scoring hits in this library was synthesized and characterized for MCHr1 antagonism, where it exhibited at least a threefold improvement in binding affinity and cellular potency relative to the parent MCHr1 ligand. This work demonstrates that the use of shape and electrostatic similarity matching in combination with a well-designed virtual library can be used to augment standard medicinal chemistry techniques.

Scaffold oriented synthesis. Part 1: Design, preparation, and biological evaluation of thienopyrazoles as kinase inhibitors.

We report the synthesis of kinase targeted libraries based on the thienopyrazole scaffold. Several thienopyrazole analogs have been identified as submicromolar inhibitors of KDR.

Design, synthesis and bioactions of novel stable mimetics of lipoxins and aspirin-triggered lipoxins.

The lipoxins (LX) are a class of potent endogenous oxygenated products that are enzymatically generated from arachidonic acid and have novel anti-inflammatory properties and promote resolution. Elucidation of the biochemical pathways involved in the metabolic inactivation of LX and the discovery of the aspirin-triggered lipoxins (ATL) provided the basis for the design and synthesis of stable analogs of LX and ATL. This special issue review describes the efforts that led to the design and synthesis of stable LX/ATL mimetics, which permitted the detailed elucidation of their novel biological roles, leading to the development of new anti-inflammatory agents that mimic their actions. These synthetic molecules provided the means to uncover the physiologic roles of both the LX and the ATL biosynthetic pathways which led to several unexpected discoveries. Among these findings is the involvement of polyisoprenyl phosphates (PIPP) in intracellular signaling mediated by presqualene diphosphate (PSDP), and the recognition of the novel roles of these lipid mediators in regulating cell trafficking during inflammation as well as in promoting resolution of inflammatory processes. These efforts also provided the basis for examining the potential therapeutic role of LX/ATL stable mimetics and led to the development of new analogs with improved pharmacokinetics that opened the way to potentially new approaches to treating human diseases.