scholarly journals Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4907
Author(s):  
Datong Zhang ◽  
He Gong ◽  
Fancui Meng
Keyword(s):  
Clinical Trials ◽  
Autoimmune Diseases ◽  
Chemokine Receptors ◽  
Rational Design ◽  
Cell Receptor ◽  
Phase 3 ◽  
Reversible Inhibitors ◽  
Irreversible Inhibitors ◽  
Promising Therapeutic Approach ◽  
Btk Inhibitors

Bruton’s tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein–inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors.

scholarly journals Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase

2020 ◽  
Vol 21 (21) ◽  
pp. 8006
Author(s):  
Eun Lee ◽  
Hyewon Cho ◽  
Da Kyung Lee ◽  
JuHyun Ha ◽  
Byeong Jo Choi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Unmet Need ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Type Ii ◽  
Irreversible Inhibitor ◽  
Bruton's Tyrosine Kinase ◽  
Irreversible Inhibitors ◽  
Btk Inhibitors

As a member of the tyrosine protein kinase Tec (TEC) family, Bruton’s tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure–activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.

Efficacy of Certolizumab Pegol for Psoriasis of the Head and Neck in Two Phase 3 Clinical Trials: CIMPASI-1 and CIMPASI-2

2019 ◽  
Vol 3 ◽  
pp. S40
Author(s):  
P Van de Kerkhof ◽  
A Pinter ◽  
M Boehnlein ◽  
S Kavanagh ◽  
J.J. Crowley
Keyword(s):  
Clinical Trials ◽  
Head And Neck ◽  
Certolizumab Pegol ◽  
Phase 3 ◽  
Two Phase

Abstract not available.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

New Anti-VEGF Drugs in Ophthalmology

2020 ◽  
Vol 21 (12) ◽  
pp. 1194-1200
Author(s):  
Claudio Campa
Keyword(s):  
Clinical Trials ◽  
Delivery System ◽  
Clinical Development ◽  
Advanced Stage ◽  
Phase 3 ◽  
Anti Vegf

: This review focuses on 5 new anti-VEGF drugs in the advanced stage of clinical development (i.e., phase 3): conbercept, brolucizumab, port delivery system with ranibizumab, abicipar pegol and faricimab. : Results of clinical trials and the advantages of each drug compared to the available molecules are discussed in detail.

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