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Product News | ACS Fall 2023 Debuts Heavyweight R&D Results (3/3)

Sep.27.2023

The most eye-catching event for medicinal chemists in August was the American Chemical Society (ACS) 2023 Annual Meeting in autumn, during which the latest research results announced by pharmaceutical manufacturers touched every nerve of medicinal chemistry practitioners.

Part 01 

GDC-6599 (Genetech)

Part 01
 
GDC-6599 (Genetech)

TRPA1 (Transient Receptor Potential Ankyrin 1) is highly expressed in sensory neurons and is a multimodal sensor that perceives endogenous and exogenous stimuli. Studies have shown that TRPA1 is associated with neuropathic pain and respiratory disorders, making it an important target for anti-inflammatory and analgesic therapy.
However, in preclinical studies, some TRPA1 antagonists have been found to cause prolonged clotting times, which Genetech attributes to the formation of aldolase metabolites in vivo by previous TRPA1 antagonists that share the same pharmacophore as known anticoagulants (e.g., coumarin, indolone).
By modifying previous TRPA1 antagonists, Genetech has developed a "First-In-Class" TRPA1 antagonist, GDC-6599, which is currently in Phase 2 clinical development for chronic cough.

TRPA1 (Transient Receptor Potential Ankyrin 1) is highly expressed in sensory neurons and is a multimodal sensor that perceives endogenous and exogenous stimuli. Studies have shown that TRPA1 is associated with neuropathic pain and respiratory disorders, making it an important target for anti-inflammatory and analgesic therapy.

 

However, in preclinical studies, some TRPA1 antagonists have been found to cause prolonged clotting times, which Genetech attributes to the formation of aldolase metabolites in vivo by previous TRPA1 antagonists that share the same pharmacophore as known anticoagulants (e.g., coumarin, indolone).

 

By modifying previous TRPA1 antagonists, Genetech has developed a "First-In-Class" TRPA1 antagonist, GDC-6599, which is currently in Phase 2 clinical development for chronic cough.

Part 02

RPT-193

(RAPT Therapeutics)

Th2 (T helper type 2) is a subset of T lymphocytes in the immune system. In the body's immune response, Th2 cells are primarily responsible for promoting the proliferation and differentiation of B cells or for causing B cells to produce various types of antibodies. In some cases, abnormalities such as excessive expression of CCR4 (C-C chemokine receptor type 4) or excessive levels of CCL17 or CCL22, the natural ligands of CCR4, in the internal environment occur in Th2 cells, leading to excessive production of interleukins such as IL4, IL5, and IL13 by Th2, which can in turn triggering an inflammatory response or asthma.

 

 

RAPT Therapeutics has designed a highly potent and orally effective CCR4 receptor antagonist, RPT-193, and has completed a Phase 1 clinical trial of RPT-193, in which the drug demonstrated excellent efficacy.RAPT Therapeutics is continuing to develop RPT-193 for the treatment of asthma and atopic diseases. RAPT Therapeutics is currently continuing Phase 2 studies of RPT-193 for the treatment of asthma and atopic dermatitis.

Part 03

EDI-048(Novartis)

Cryptosporidiosis, a diarrhoeal disease, is one of the leading causes of death in children under 2 years of age in less developed countries. The only drug currently approved for the treatment of Cryptosporidiosis is nitazodone, but its efficacy is weak.

 

The use of CpPI(4)K (Cryptosporidium PI(4)K) inhibitors to interfere with Cryptosporidium synthesis of cell membranes is effective in inhibiting parasite reproduction; however, CpPI(4)K has a high degree of homology with human lipid kinases, such as PI(4)KIIIβ, and thus the use of CpPI(4)K inhibitors may lead to numerous side effects.

 

 

In order to overcome the potential side effects of CpPI(4)K inhibitors, Novartis applied a "soft-drug" strategy to the design of this class of drugs, resulting in the design of a "First-In-Class" cryptogenic drug. EDI-048, a "First-In-Class" cryptosporidiosis drug, was designed to concentrate the active form of the drug on the surface of the intestinal tract with little or no distribution to the rest of the body, and has demonstrated a high degree of safety in preclinical studies, and is currently in Phase 1 clinical studies.

Part 04

PF-07817883(Pfizer)

The well-known COVID-19 treatment Paxlovid is a combination of the antiviral drug Nirmatrelvir, an inhibitor of the SARS-CoV-2 master protease (also known as Mpro, 3CLpro, nsp5 protease), and the metabolic inhibitor Ritonavir. Ritonavir is a potent CYP3A inhibitor.

 

Nirmatrelvir is the main active ingredient in Paxlovid, and Ritonavir enhances the activity of Nirmatrelvir by inhibiting its metabolism. Based on the structure of Nirmatrelvir, Pfizer has developed a new generation of SARS-CoV-2 master protease inhibitor, PF-07817883.

 

 

In vitro data suggest a low risk of drug-drug interactions when PF-07817883 is used alone, and metabolic stability data indicate that PF-07817883 can be used alone without the need for a CYP3A inhibitor. PF-07817883 is currently in Phase 2 clinical studies.

 

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Cryptosporidiosis, a diarrhoeal disease, is one of the leading causes of death in children under 2 years of age in less developed countries. The only drug currently approved for the treatment of Cryptosporidiosis is nitazodone, but its efficacy is weak.
The use of CpPI(4)K (Cryptosporidium PI(4)K) inhibitors to interfere with Cryptosporidium synthesis of cell membranes is effective in inhibiting parasite reproduction; however, CpPI(4)K has a high degree of homology with human lipid kinases, such as PI(4)KIIIβ, and thus the use of CpPI(4)K inhibitors may lead to numerous side effects.

 

In order to overcome the potential side effects of CpPI(4)K inhibitors, Novartis applied a "soft-drug" strategy to the design of this class of drugs, resulting in the design of a "First-In-Class" cryptogenic drug. EDI-048, a "First-In-Class" cryptosporidiosis drug, was designed to concentrate the active form of the drug on the surface of the intestinal tract with little or no distribution to the rest of the body, and has demonstrated a high degree of safety in preclinical studies, and is currently in Phase 1 clinical studies.
Th2 (T helper type 2) is a subset of T lymphocytes in the immune system. In the body's immune response, Th2 cells are primarily responsible for promoting the proliferation and differentiation of B cells or for causing B cells to produce various types of antibodies. In some cases, abnormalities such as excessive expression of CCR4 (C-C chemokine receptor type 4) or excessive levels of CCL17 or CCL22, the natural ligands of CCR4, in the internal environment occur in Th2 cells, leading to excessive production of interleukins such as IL4, IL5, and IL13 by Th2, which can in turn triggering an inflammatory response or asthma.

 

RAPT Therapeutics has designed a highly potent and orally effective CCR4 receptor antagonist, RPT-193, and has completed a Phase 1 clinical trial of RPT-193, in which the drug demonstrated excellent efficacy.RAPT Therapeutics is continuing to develop RPT-193 for the treatment of asthma and atopic diseases. RAPT Therapeutics is currently continuing Phase 2 studies of RPT-193 for the treatment of asthma and atopic dermatitis.
Th2 (T helper type 2) is a subset of T lymphocytes in the immune system. In the body's immune response, Th2 cells are primarily responsible for promoting the proliferation and differentiation of B cells or for causing B cells to produce various types of antibodies. In some cases, abnormalities such as excessive expression of CCR4 (C-C chemokine receptor type 4) or excessive levels of CCL17 or CCL22, the natural ligands of CCR4, in the internal environment occur in Th2 cells, leading to excessive production of interleukins such as IL4, IL5, and IL13 by Th2, which can in turn triggering an inflammatory response or asthma.

 

RAPT Therapeutics has designed a highly potent and orally effective CCR4 receptor antagonist, RPT-193, and has completed a Phase 1 clinical trial of RPT-193, in which the drug demonstrated excellent efficacy.RAPT Therapeutics is continuing to develop RPT-193 for the treatment of asthma and atopic diseases. RAPT Therapeutics is currently continuing Phase 2 studies of RPT-193 for the treatment of asthma and atopic dermatitis.
Th2 (T helper type 2) is a subset of T lymphocytes in the immune system. In the body's immune response, Th2 cells are primarily responsible for promoting the proliferation and differentiation of B cells or for causing B cells to produce various types of antibodies. In some cases, abnormalities such as excessive expression of CCR4 (C-C chemokine receptor type 4) or excessive levels of CCL17 or CCL22, the natural ligands of CCR4, in the internal environment occur in Th2 cells, leading to excessive production of interleukins such as IL4, IL5, and IL13 by Th2, which can in turn triggering an inflammatory response or asthma.

 

RAPT Therapeutics has designed a highly potent and orally effective CCR4 receptor antagonist, RPT-193, and has completed a Phase 1 clinical trial of RPT-193, in which the drug demonstrated excellent efficacy.RAPT Therapeutics is continuing to develop RPT-193 for the treatment of asthma and atopic diseases. RAPT Therapeutics is currently continuing Phase 2 studies of RPT-193 for the treatment of asthma and atopic dermatitis.
Th2 (T helper type 2) is a subset of T lymphocytes in the immune system. In the body's immune response, Th2 cells are primarily responsible for promoting the proliferation and differentiation of B cells or for causing B cells to produce various types of antibodies. In some cases, abnormalities such as excessive expression of CCR4 (C-C chemokine receptor type 4) or excessive levels of CCL17 or CCL22, the natural ligands of CCR4, in the internal environment occur in Th2 cells, leading to excessive production of interleukins such as IL4, IL5, and IL13 by Th2, which can in turn triggering an inflammatory response or asthma.

 

RAPT Therapeutics has designed a highly potent and orally effective CCR4 receptor antagonist, RPT-193, and has completed a Phase 1 clinical trial of RPT-193, in which the drug demonstrated excellent efficacy.RAPT Therapeutics is continuing to develop RPT-193 for the treatment of asthma and atopic diseases. RAPT Therapeutics is currently continuing Phase 2 studies of RPT-193 for the treatment of asthma and atopic dermatitis.
Th2 (T helper type 2) is a subset of T lymphocytes in the immune system. In the body's immune response, Th2 cells are primarily responsible for promoting the proliferation and differentiation of B cells or for causing B cells to produce various types of antibodies. In some cases, abnormalities such as excessive expression of CCR4 (C-C chemokine receptor type 4) or excessive levels of CCL17 or CCL22, the natural ligands of CCR4, in the internal environment occur in Th2 cells, leading to excessive production of interleukins such as IL4, IL5, and IL13 by Th2, which can in turn triggering an inflammatory response or asthma.

 

RAPT Therapeutics has designed a highly potent and orally effective CCR4 receptor antagonist, RPT-193, and has completed a Phase 1 clinical trial of RPT-193, in which the drug demonstrated excellent efficacy.RAPT Therapeutics is continuing to develop RPT-193 for the treatment of asthma and atopic diseases. RAPT Therapeutics is currently continuing Phase 2 studies of RPT-193 for the treatment of asthma and atopic dermatitis.