Thomas Nixey

Selective inhibitors of the mutant B-raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.

The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.

Two-step solution-phase synthesis of novel quinoxalinones utilizing a UDC (Ugi/de-Boc/cyclize) strategy

Abstract The novel solution-phase synthesis of an array of biologically relevant quinoxalinones in a simple two-step procedure is revealed. Transformations are carried out in excellent yield by condensation of mono-Boc protected ortho -phenylene di-amine, glyoxylic acids and supporting Ugi reagents. Subsequent acid treatment and evaporation affords quinoxalinones in good to excellent yields.

The one-pot solution phase preparation of fused tetrazole-ketopiperazines

Abstract A novel application of the TMSN 3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused tetrazole-ketopiperazine libraries. The reaction of an aldehyde, primary amine, methyl isocyanoacetate and trimethylsilylazide in methanol at reflux affords bicyclic tetrazole-ketopiperazines in good yield. This efficient one step protocol, producing products with three potential diversity points, may be used to generate arrays of biologically relevant small molecules for general and targeted screening.

Short solution phase preparation of fused azepine-tetrazoles via a UDC (Ugi/de-Boc/cyclize) strategy ☆

Abstract A novel application of the TMSN 3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused azepine-tetrazole libraries. The reaction of a N -Boc-α-amino aldehyde, secondary amine, methyl isocyanoacetate and trimethylsilylazide in methanol, followed by acid treatment, proton scavenging and reflux affords bicyclic azepine-tetrazoles. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for general and targeted screening.

Rapid generation of cis-constrained norstatine analogs using a TMSN3-modified Passerini MCC/N-capping strategy

A novel application of the TMSN3-modified Passerini three-component reaction is disclosed for the rapid solution phase synthesis of cis constrained norstatine mimetic libraries. The reaction of an N-BOC-α-amino aldehyde, an isocyanide and trimethylsilylazide in dichloromethane, followed by deprotection and N-capping with TFP esters affords cis constrained norstatine mimetics. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for protease targeted screening.

Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer.

A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC-MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K(D)) and PDE10A target density (B(max)) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [(3)H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [(3)H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC-MS/MS technology.

Library Generation via Postcondensation Modifications of Isocyanide-Based Multicomponent Reactions

Publisher Summary This chapter focuses on a particular branch of multicomponent condensation reaction (MCR) methodologies— namely, the postcondensation modifications (or secondary reactions) of isocyanide-based multicomponent reactions (IMCRs). One attractive feature of the multicomponent reaction is the relative ease of its automation. Discrete reactions may be run in parallel by either solution- or solid-phase protocols in a standard 96-well format. One of the methodologies discussed in the chapter is the UDC (Ugi/De-Boc/Cyclize) methodology. The biological utility of 1,4-benzodiazepine-2,5-diones (BDPs) appears in many areas, including the applications as antagonists of the platelet glycoprotein IIb-IIIa, anticonvulsant agents, antihypnotic agents, reverse transcriptase inhibitors, and selective cholecystokinin (CCK) receptor subtype A or B antagonists. The chapter presents three miscellaneous postcondensation modification reactions: (1) TMSN 3 modified Ugi Reactions, (2) postcondensation Passerini reactions, and (3) TMSN 3 -modified Passerini reaction. The TMSN 3 -modified Ugi reaction involves the condensation of an appropriately substituted aldehyde or ketone with a primary or secondary amine.

Discovery of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines as potent PIM inhibitors.

PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.

One-pot microwave assisted preparation of pyrazoloquinazolinone libraries

The novel solution phase synthesis of an array of biologically relevant pyrazoloquinazolinones in a simple microwave driven, one pot procedure is described. Transformations are carried out in good to excellent yield by condensation of α-cyano-ketones and 2-hydrazino-benzoic acids. Subsequent microwave irradiation affords pyrazoloquinazolinones with six points of potential diversification. The protocol described represents a very attractive solution phase procedure for the rapid generation of arrays of such functionalized cores, further demonstrating the growing importance of economic al chemistries that enable complexity to the genered in this leading arena.

The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors.

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compounds potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55nM and 0.28nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50=150nM). This compound had moderate clearance and bioavailability in rat (CL=2.42L/kg/h; %F=24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74μM (18μg/mL) when dosed at 10, 30, 100 and 200mg/kg po in mice.