Chandrasekhar Abbineni

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.

A mild and convenient indium(III) chloride-catalyzed synthesis of thioglycosides

The efficiency of glycosidation reactions generally involves a high chemical yield, as well as high/complete stereo- and regioselectivity. All these depend on the compatibility of the reactivity of glycosyl donors and acceptors. Among glycosyl donors, thioglycosides are widely used because of their high degree of stability in many organic reactions. Although there are number of methods available for the preparation of thioglycosides, all of them have one or more disadvantages, especially concerning the time factor and cumbersome workup procedures. Here we report a convenient and high-yielding method for the preparation of thioglycosides.

Microwave-induced, InCl3-catalyzed ferrier rearrangement of acetylglycals: synthesis of 2,3-unsaturated C-glycosides

Abstract Indium(III) chloride-catalyzed, microwave-assisted Ferrier rearrangement of different per-O-acetylglycals leads to an efficient synthesis of 2,3-unsaturated C-glycosides in good to excellent yields.

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.

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.

Novel thieno oxazine analogues as antihyperglycemic and lipid modulating agents

A series of phenyl acetic acid and alpha-hydroxy propionic acid derivatives were synthesized. In vivo studies of the compounds indicated compound 2c as the most potent in one of the series, which has both glucose and lipid lowering properties. The syntheses and biological studies have been discussed.

Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

Abstract LB-113: Immune-mediated anti-tumor activity with a clinical stage BET bromodomain inhibitor ODM-207 in pre-clinical models

Background: ODM-207 is a potent and selective BET inhibitor that is structurally unrelated to the benzodiazepine-based inhibitors including JQ1, I-BET762, and OTX015. Phase I clinical trials have now been initiated with this agent based on its potent anti-tumor activity in various in vitro and in vivo models of hematologic malignancies and solid tumors. In view of the recent publications implicating a role for BET protein BRD4 in the suppression of PD-L1 expression, an immune checkpoint ligand for PD-1, we sought to evaluate ODM-207 for its effect on immune-mediated anti-tumor efficacy in pre-clinical models. Methods and Results: Mouse splenocytes were stimulated with anti-CD3 and anti-CD28 in the presence or absence of ODM-207 for four days and changes in immune cell population were analyzed by FACS. Results revealed an increase in the level of activated cytotoxic CD8+ T cells as indicated by increased intracellular IFNγ and granzyme B with ODM-207 treatment. After confirming the lack of direct anti-proliferative activity on the mouse colon carcinoma cell line CT26, in vivo evaluation of ODM-207 was carried out in the syngeneic CT26 subcutaneous tumor model established in BALB/c mice. Daily oral administration of ODM-207 at 30 mg/kg was well tolerated in this model and resulted in a statistically significant inhibition of tumor growth. Interestingly, the tumor growth inhibition observed with ODM-207 was comparable to that with a commercially available anti-mouse PD1 antibody. Studies to characterize the immune changes in the tumor and anti-tumor activity of ODM-207 in combination with an anti-mouse PD1 antibody are currently underway and the results will be presented. Conclusions: In summary, these studies demonstrate the anti-tumor activity of BET inhibitor in a syngeneic model of colon carcinoma in the absence of a direct anti-proliferative activity on tumor cells. Observed tumor growth inhibition correlated with the in vitro activation of cytotoxic CD8+ T cells supporting the immune-mediated effect leading to tumor growth inhibition. In view of the remarkable success with the immune-based therapeutic approaches, these findings are relevant in devising appropriate strategies for the continued clinical development of ODM-207. Citation Format: Pratima Deshpande, Ravi Krishna Babu, Prashant Yallappa Vadnal, Mahaboobi Jaleel, Murali Ramachandra, Chandrasekhar Abbineni, Susanta Samajdar, Anu-Maarit Moilanen, Pekka Kallio. Immune-mediated anti-tumor activity with a clinical stage BET bromodomain inhibitor ODM-207 in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-113. doi:10.1158/1538-7445.AM2017-LB-113

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