Evidence map›Paper›PMID 38746903›Full record

ArticleACS medicinal chemistry letters2024

A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.

Philippe N Bolduc, Magnus Pfaffenbach, Ryan Evans, Zhili Xin, Kate L Henry, Fang Gao, Terry Fang, John Silbereis, Jorge Vera Rebollar, Pei Li and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ACS medicinal chemistry letters, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Philippe N BolducDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.ORCID https://orcid.org/0000-0001-8726-4364
Magnus PfaffenbachDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.ORCID https://orcid.org/0000-0002-0068-6829
Ryan EvansDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Zhili XinDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Kate L HenryDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Fang GaoDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Terry FangDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
John SilbereisDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Jorge Vera RebollarDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Pei LiDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.ORCID https://orcid.org/0000-0003-0634-5213
Jayanth V ChodaparambilDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Claire MetrickDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Emily A PetersonDepartment of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.ORCID https://orcid.org/0000-0001-5854-2505

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

Identifiers

PMID38746903
PMCPMC11089553

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.