Practial isolation of the (1R,2R)-enantiomer from a racemic cis/trans mixture of 2-methylcyclohexyl-1-amine

2-Methylcyclohexyl-1-amine exists in four stereoisomeric forms. Although it is a simple compound, none of the stereoisomers is readily available in its pure form. Four synthetic routes are described in the literature for the preparation of the trans-enantiomers in 4-8 steps. In addition, one enzyme based transformation led to pure enantiomers in one step, although as a cis/trans mixture. We herein described a crystallization method identified by a diastereomeric salt screen allowing the isolation of a single trans enantiomer from a cheap commercial source consisting of a mixture of all four stereoisomers

Practical Isolation of the (1<i>R</i>,2<i>R</i>)‑Enantiomer from a Racemic <i>cis/trans</i> Mixture of 2‑Methyl-1-cyclohexanamine

2-Methyl-1-cyclohexanamine exists in four stereoisomeric forms. Although it is a simple compound, none of the stereoisomers is readily available in its pure form. We herein described a crystallization method identified by a salt screen (diastereomeric salt formation) allowing the isolation of a single <i>trans</i> enantiomer from a readily available commercial source consisting of a mixture of all four stereoisomers

Scale up synthesis of IID572: A new β-lactamase inhibitor

The new potentially best-in-class β-lactamase inhibitor IID572 was discovered by a late stage functionalization approach. An alternative scalable synthesis was developed to satisfy the short-term need for tox studies. The two key features were an intramolecular azomethine ylide [2+3] cycloaddition that allowed the quick formation of molecular complexity from cheap starting material and an efficient enzymatic resolution that resulted in high optical purity of a key intermediate

Synthesis of All Four Stereoisomers of 3‑(<i>tert</i>-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic Acid

A synthesis of all four stereoisomers of 3-(<i>tert</i>-butoxycarbonyl)-3-azabicyclo­[3.1.0]­hexane-2-carboxylic acid has been developed, thereby significantly shortening the known literature procedures for the syntheses of these unnatural amino acids. With a simple adjustment of the reaction conditions, we were able to obtain either pure <i>cis</i> or <i>trans</i> acid. Optical resolution was accomplished via diastereomeric salt formation or alternatively via chromatography on a chiral stationary phase. Finally, <i>ab initio</i> calculations gave an explanation for the observed <i>cis</i> selectivity in the initial step

Improving non-specific binding and solubility: bicycloalkyl groups and cubanes as para-phenyl bioisosteres

Bicycloalkyl groups have previously been described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction in complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves solubility by at least 50-fold, and markedly decreases non-specific binding (NSB) as measured using CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits with regard to non-specific binding or solubility, whereas substitutions with cubane-1,4-diyl also showed an improvement in both parameters. These results confirm the potential advantages of both BCP and cubane groups as bioisosteric replacements for optimizing para-phenyl substituted molecules

IID572: A New Potentially Best-In-Class β-Lactamase Inhibitor

Resistance in Gram-negative bacteria to β-lactam drugs is mediated primarily by the expression of β-lactamases, and co-dosing of β-lactams with a β-lactamase inhibitor (BLI) is a clinically proven strategy to address resistance. New β-lactamases that are not impacted by existing BLIs are spreading and creating the need for development of novel broader spectrum BLIs. IID572 is a novel broad spectrum BLI of the diazabicyclooctane (DBO) class that is able to restore the antibacterial activity of piperacillin against piperacillin/tazobactam-resistant clinical isolates. IID572 is differentiated from other DBOs by its broad inhibition of β-lactamases and the lack of intrinsic antibacterial activity

7-Azaindole-3-acetic acid derivatives: potent and selective CRTh2 receptor antagonists

High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished NVP-QAV680, a highly selective compound with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development

Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization

Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary study were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbonate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in-vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using non-cleavable linkers, and the resulting conjugates (ADC-4, ADC-11 and ADC-12) led to in-vivo efficacy in a HER-2 expressing (SK-OV-3ip) mouse xenograft model in a target-dependent manner

Concise synthesis of all four stereoisomers of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

A concise synthesis of all four stereoisomers of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid has been developed; thereby significantly shortening the known literature procedures for the syntheses of these unnatural amino acids. With a simple adjustment of the reaction conditions, we were able to obtain either pure cis or trans acid. Optical resolution was accomplished via diastereomeric salt formation or alternatively via chromatography on a chiral stationary phase. Finally, ab-initio calculations gave an explanation for the observed cis selectivity in the initial step