Rational Design of a Topical Androgen Receptor Antagonist for the Suppression of Sebum Production with Properties Suitable for Follicular Delivery

Mitchell, Lorna H.; Johnson, Theodore R.; Lu, Guang Wei; Du, Daniel; Datta, Kaushik; Grzemski, Felicity A.; Shanmugasundaram, Veerabahu; Spence, Julie; Wade, Kim; Zhi, Wang; Sun, Kevin Kai; Lin, Kristin; Hu, Lufei; Sexton, Karen E.; Raheja, Neil; Kostlan, Catherine R.; Pocalyko, David

doi:10.1021/jm9018004

Cited by 12 publications

(5 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mesocricetus auratus was selected as experimental animal in both studies because growth factors would be readily absorbed reaching systemic circulation after its topical application. Thus, this could be a suitable animal model to study efficacy and safety of IGF-1 and VEGF [9]. …”

Section: Discussionmentioning

confidence: 99%

Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model

et al. 2013

View full text Add to dashboard Cite

BackgroundAlopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects.MethodsMesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex® gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done.ResultsAt the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert.ConclusionsVEGF increased hair follicle area, but more studies are necessary to confirm its toxicity.

show abstract

Section: Discussionmentioning

confidence: 99%

Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model

et al. 2013

View full text Add to dashboard Cite

show abstract

“…In order to reduce the risk of various side effects associated with the systemic exposure of topical agents, a high hepatic clearance of topical agents is crucial. − Compounds 13i and 18k were selected for further evaluation of in vitro metabolic stability in mouse liver microsomes (MLM) and human liver microsomes (HLM), with verapamil used as a positive control (see Table ). In HLM, both 13i and 18k showed comparable clearance rates to verapamil, while in MLM, their clearance rates were significantly lower.…”

Section: Resultsmentioning

confidence: 99%

Discovery of (2S)-N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(6-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-hydroxy-2-methylpropanamide as a Highly Potent and Selective Topical Androgen Receptor Antagonist for Androgenetic Alopecia Treatment

Zhang,

Zhao,

Luo

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

Androgenetic alopecia (AGA) is the most prevalent form of progressive hair loss disorder in both men and women, significantly impacting their appearance and overall quality of life. Overactivation of the AR signaling pathway in dermal papilla cells (DPCs) plays a crucial role in the development and progression of AGA. Considering the severe systemic side effects associated with oral AR antagonists, the idea of developing of topical AR antagonists with rapid metabolic deactivation properties emerged as a promising approach. Herein, through systematic structural optimization, we successfully identified compound 30a as a potent and selective AR antagonist with favorable pharmacokinetic properties, resulting in high skin exposure and low plasma exposure following topical administration. Importantly, in both hair-growth and AGA mouse models, compound 30a showed potent hair-growth-promoting effects without any noticeable toxicity. These findings suggest that compound 30a holds significant potential as a topical AR antagonist for treating AGA patients.

show abstract

“…Pfizer reported a series of AR antagonists ( 100 – 106 ) (Figure ). − These compounds have hAR binding IC 50 values of 20 to 100 nM and AR MDA-kb2 cell function IC 50 values from 0.2 to 90 nM (Table ). Most of these compounds reduce wax ester in an animal topical sebum model, but none of them has been evaluated in the clinic.…”

Section: Androgen-competitive Antagonistsmentioning

confidence: 99%

Therapeutic Strategies to Target the Androgen Receptor

Xiang

Wang

2022

J. Med. Chem.

View full text Add to dashboard Cite

The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

show abstract

Rational Design of a Topical Androgen Receptor Antagonist for the Suppression of Sebum Production with Properties Suitable for Follicular Delivery

Cited by 12 publications

References 40 publications

Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model

Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model

Discovery of (2S)-N-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(6-(4-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-hydroxy-2-methylpropanamide as a Highly Potent and Selective Topical Androgen Receptor Antagonist for Androgenetic Alopecia Treatment

Therapeutic Strategies to Target the Androgen Receptor

Contact Info

Product

Resources

About