In This Issue Cite This: ACS Med. Chem. Lett. 2018, 9, 65−65
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MICROSOMAL OXIDATION IS A POWERFUL APPROACH TO RAPIDLY IDENTIFY ANALOGUES WITH IMPROVED PROPERTIES IN LATE-STAGE PROGRAMS
C−H functionalization strategies have emerged recently as a means to rapidly explore structure−activity relationships and address metabolic liabilities in late-stage lead optimization programs. In the present issue, Stepan et al. (DOI: 10.1021/ acsmedchemlett.7b00343) describe a strategy for using liver microsomes in place of traditional medicinal chemistry to rapidly generate C−H derivatives. Specifically, they applied this methodology to a PDE2 inhibitor lead compound that was potent but showed significant CYP3A4 liability. This is typical of the type of late-stage problems that can derail an otherwise successful discovery program. Incubation with monkey liver microsomes provided three new hydroxylated analogues. One of these analogues, PF-06815189, was scaled up using conventional synthesis and found to provide an improved pharmacological profile. This promising approach is particularly applicable to latestage programs with potential drug−drug interaction liabilities.
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SYNTHESIS OF RIGID CXCR4 ANTAGONISTS LEADS TO POTENT COMPOUNDS WITH FEWER DEVELOPMENT LIABILITIES One of the most therapeutically important chemokine receptors is CXCR4. It has been implicated in a wide range of diseases, most notably metastatic cancer. Progress has been impeded by the difficult task of balancing potency with the other properties necessary for a commercial drug. Jecs et al. (DOI: 10.1021/ acsmedchemlett.7b00406) present a systematic synthetic approach for improving the pharmacological properties of an otherwise potent CXCR4 antagonist. They hypothesized that a more rigid antagonist would be less susceptible to metabolism in the rat, a necessity for preclinical studies, and potentially have improved intestinal permeability. By introducing progressively more rigid amino side chains, they mapped out a series of analogues with improved pharmacological profiles. These compounds and the corresponding structure−activity relationship information represent meaningful progress against a clinically valuable target.
UNIQUE NMR CHARACTERISTICS OF LIGANDS WITH TERT-BUTYL GROUPS CAN BE EXPLOITED TO IDENTIFY LIGAND-BINDING SITES IN PROTEINS
A common situation in drug discovery is to have a protein crystal structure for the target of interest, but not with the lead ligand bound. NMR can be employed to potentially determine the ligand binding site, but this can be an arduous process that may require protein labeling and a ligand with specific binding kinetics. Chen and Otting outline an approach (DOI: 10.1021/ acsmedchemlett.7b00464) that exploits the unique 1H NMR signal of tert-butyl substituents to rapidly identify the location of ligand binding. This methodology requires the presence of a tertbutyl group in the ligand but does not require any prior analysis of the protein NMR structure. The authors present a validation study using the complex of hepatitis C inhibitor, asunaprevir (BMS-650032), and NS4A-NS3. Their analysis of this ligand− protein complex demonstrates the potential of this NMR method to identify protein binding sites for tight-binding ligands, without resorting to perdeuteration of the protein. © 2018 American Chemical Society
Published: February 8, 2018 65
DOI: 10.1021/acsmedchemlett.8b00034 ACS Med. Chem. Lett. 2018, 9, 65−65
