Sanjita Sasmal

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Part 2 ☆

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.

Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.

3-alkoxy-pyrrolo[1,2-b]pyrazolines as selective androgen receptor modulators with ideal physicochemical properties for transdermal administration

We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed high aqueous solubility of 1.3 g/L at pH 7.4, and an in silico model as well as a customized parallel artificial membrane permeability assay indicated good skin permeation. Indeed, when measuring skin permeation through excised human skin, an excellent flux of 2 μg/(cm(2)·h) was determined without any permeation enhancers. In a 2 week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation.

Synthesis and SAR studies of benzimidazole derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: Focus to detune hERG inhibition

Melanin concentrating hormone receptor 1 (MCHR1) antagonists are potentially useful in the treatment of several CNS disorders such as obesity, stress, depression and anxiety. In a previous article, we have described a novel series of benzimidazoles as MCHR1 antagonists. These compounds showed good efficacy in obesity models but the lead compound also showed potent inhibition of hERG potassium channel. Described herein the medicinal chemistry attempts to reduce hERG inhibition while retaining MCHR1 antagonistic profile.

Abstract 671: Identification of potent BET bromodomain inhibitors for treatment of cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression. Histone lysine acetylation is one of the most abundant epigenetic modifications central to control of gene transcription. Bromodomains are the only known readers of this specific lysine acetylation code, playing an important role in transcriptional regulation of diverse cellular processes such as inflammatory gene expression, mitosis and viral/host interactions. Recently, the human BET family bromodomains which consists of BRD2, BRD3, BRD4 and BRDT has emerged as new druggable target class for the development of specific protein interaction inhibitors, enabling a novel strategy for the development of new therapies for various diseases. Here we report the identification of potent BET bromodomain inhibitors using structure based drug design principle. Multiple distinct series of compounds have been identified with low nM potency in biochemical binding assay. Crystal structures of BRD4 in complex with hit compounds have been solved to assist in optimization. The lead compounds showed very good cell based activity and favorable ADME properties. The compounds demonstrated dose dependent inhibition of c-Myc expression confirming the mechanism of action. Further optimization of these compounds and profiling in relevant pre-clinical disease models is in progress. Citation Format: Sanjita Sasmal, Rajeev Kumar Shrimali, Chandrasekhar Abbineni, Kamala Kumari Arumalla, Anirudha Lakshminarasimhan, Karthikeyan Narasingapuram Arumugam, Nirbhay Kumar Tiwari, Narasimha K. Rao, Aravind AB, Subramanya Hosahalli. Identification of potent BET bromodomain inhibitors for treatment of cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 671. doi:10.1158/1538-7445.AM2013-671