Optimization of the efflux ratio and permeability of covalent irreversible BTK inhibitors

Qiu, Hao; Liu-Bujalski, Lesley; Caldwell, Richard D.; Follis, Ariele Viacava; Gardberg, A.S.; Goutopoulos, Andreas; Grenningloh, Roland; Head, Jared; Johnson, Theresa; Jones, Christopher C.; Jones, Reinaldo; Mochalkin, Igor; Morandi, Federica; Neagu, Constantin; Potnick, Justin R.; Sherer, Brian

doi:10.1016/j.bmcl.2018.09.018

Cited by 5 publications

(15 citation statements)

References 30 publications

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“…Although the design of potent and selective probes based on the scaffold of the pyridine carboxamide SAP series seemed feasible, we were concerned about the permeability of the probes, because the addition of heteroatom‐containing linkers and reporting groups would dramatically increase the topological polar surface area (tPSA) of the probe molecules. In our former exploration of pyridine carboxamide SAP series, we observed that molecules with a tPSA value >125.7 Å 2 might have limited cell permeability, indicated by high efflux ratio (ER>3) and low A→B rate (<1×10 −6 cm s −1 ) in Caco‐2 assays . However, we did observe that installation of steric hindrance might be applied to reduce ER.…”

Section: Figurementioning

confidence: 71%

“…In our former exploration of pyridine carboxamide SAP series, we observed that molecules with at PSA value > 125.7 2 might have limited cell permeability,i ndicated by high effluxr atio (ER > 3) and lowA !Br ate (< 1 10 À6 cm s À1 )i nC aco-2a ssays. [21,23] However, we did observe that installation of steric hindrance might be applied to reduce ER. Based on this, we hypothesized that the extended SAP group in ap robe molecule, which made it sterically bulkier than the parentm olecule, might help the probe molecule on the permeability profile.…”

mentioning

confidence: 76%

“…Unfortunately, this was challenging to achieve with this aminopyrimidine scaffold. Consequently, we ended optimization efforts in this series and redirected our efforts to explore the scaffold of a novel pyridine carboxamide solvent‐accessible pocket (SAP) series (Figure ) . Herein we present the discovery of new small‐molecule affinity‐based probes based on the pyridine carboxamide scaffold of the aforementioned series.…”

Section: Figurementioning

confidence: 99%

“…However, we did observe that installation of steric hindrance might be applied to reduce ER. Based on this, we hypothesized that the extended SAP group in a probe molecule, which made it sterically bulkier than the parent molecule, might help the probe molecule on the permeability profile …”

Section: Figurementioning

confidence: 99%

“…Consequently,w ee nded optimization efforts in this series and redirected our efforts to explore the scaffold of an ovel pyridine carboxamide solvent-accessible pocket (SAP) series ( Figure 4). [20][21][22][23] Herein we present the discovery of new small-molecule affinity-based probesb ased on the pyridine carboxamide scaffold of the aforementioned series. The top probe molecule has been used in evaluating target engagement of Btkinhibitors in preclinical studies.…”

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confidence: 99%

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Discovery of Affinity‐Based Probes for Btk Occupancy Assays

et al. 2019

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Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B‐cell malignancies and autoimmune diseases. Small‐molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent‐accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity‐based biotinylated probe 12 (2‐[(4‐{4‐[5‐(1‐{5‐[(3aS,4S,6aR)‐2‐oxo‐hexahydro‐1H‐thieno[3,4‐d]imidazol‐4‐yl]pentanamido}‐3,6,9,12‐tetraoxapentadecan‐15‐amido)pentanoyl]piperazine‐1‐carbonyl}phenyl)amino]‐6‐[1‐(prop‐2‐enoyl)piperidin‐4‐yl]pyridine‐3‐carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.

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Section: Figurementioning

confidence: 71%

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confidence: 76%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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confidence: 99%

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Discovery of Affinity‐Based Probes for Btk Occupancy Assays

et al. 2019

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Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity

Qiu

Ali

Bowlan³

et al. 2021

ChemMedChem

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Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors. The top molecule 1 of that series strongly inhibited CYP2C8 (IC50=100 nM), which was attributed to the bridged linker group. However, our effort on the linker replacement turned out to be fruitless. With the study of the X‐ray crystal structure of compound 1, we envisioned the opportunity of removal of this liability via transposition of the linker moiety in 1 from C6 to C5 position of the pyridine core. With this strategy, our optimization led to the discovery of a novel series, in which the top molecule 18 A displayed reduced CYP inhibitory activity and good potency. To further explore this new series, different warheads besides acrylamide, for example cyanamide, were also tested. However, this effort didn't lead to the discovery of molecules with better potency than 18 A. The loss of potency in those molecules could be related to the reduced reactivity of the warhead or reversible binding mode. Further profiling of 18 A disclosed that it had a strong hERG (human Ether‐a‐go‐go Related Gene) inhibition, which could be related to the phenoxyphenyl group.

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