Abstract:The phosphate prodrug approach has emerged as a viable option for increasing the bioavailability of a drug candidate with low hydrophilicity and poor cell membrane permeability. When a phosphoric acid moiety is attached to the parent drug, it results in a several-fold elevation in aqueous solubility which helps to achieve desired bioavailability of the pharmaceutically active parental molecule. The neutral phosphate prodrugs have rapid diffusion ability through the plasma membrane as compared to their charged counterpart. The presence of phosphate mono ester breaking alkaline phosphatase (ALP) enzyme throughout the whole human body, is the main consideration behind the development of phosphate prodrug strategy. The popularity of this phosphate prodrug strategy is increasing nowadays due to the fulfillment of different desired pharmacokinetic characteristics required to get pharmaceutical and therapeutic responses without showing any serious adverse drug reactions (ADR). This review article mainly focuses on various phosphate prodrugs synthesized within the last decade to get an improved pharmacological response of the parent moiety along with various preclinical and clinical challenges associated with this approach. Emphasis is also given to the chemical mechanism to release the parent moiety from the prodrug.

2018-07-20·Organic Process Research & Development

Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

作者: Gupta, Anuradha ; Kempson, James ; Wong, Michael K. Y. ; Muthalagu, Vetrichelvan ; Wu, Dauh-Rurng ; Zhang, Huiping ; Galella, Michael A. ; Rampulla, Richard ; Li, Peng ; Li, Jianqing ; Arunachalam, Pirama Nayagam ; Mathur, Arvind ; Traeger, Sarah C. ; Dabros, Marta

Methods for the preparation of the neg. allosteric glutamate N2B (GluN2B) inhibitor BMS-986169 I (R = H) and its prodrug BMS-986163 I [R = P(:O)(OH)₂] on multigram scale for use in toxicol. studies in vivo were developed.The deoxyfluorination of a (hydroxyphenyl)hydroxypiperidinecarboxylate with minimal rearrangement using Deoxofluor [bis(2-methoxyethyl)aminosulfur trifluoride] and the phosphorylation of I (R = H) with phosphoryl chloride (POCl₃) mediated by Et₃N in THF followed by hydrolysis were key steps in the preparation of I.

2018-05-10·ACS Medicinal Chemistry Letters3区 · 医学

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder

3区 · 医学

Article

作者: Nagaraju, G. ; King, Dalton ; Ng, Alicia ; Marcin, Lawrence R. ; Karageorge, George N. ; Kempson, James ; Vijaya, Kumar Kuchibhotla ; Cheruku, Srinivas ; Paschapur, Mahesh ; Islam, Imadul ; Albright, Charlie ; Shi, Jianliang ; Kamble, Manjunatha ; Zhuo, Xiaoliang ; Kallem, Rajareddy ; Li, Jianqing ; Bronson, Joanne J. ; Kalidindi, Narasimharaju ; Tonukunuru, Gopikishan ; Mannoori, Raju ; Shields, Eric ; Thompson, Lorin A. ; Simmermacher, Jean ; Reddy, Aliphedi B. ; Zhang, Huiping ; Jogi, Srinivas ; Bastia, Tanmaya ; Pearce, Bradley C. ; Macor, John E. ; Olson, Richard E. ; Aher, Jayant ; Gulia, Jyoti ; Denton, Rex ; Ramarao, Manjunath ; Sinz, Michael ; Naidu, Pattipati S. ; Thangathirupathy, Srinivasan ; Vikramadithyan, Reeba ; Warrier, Jayakumar ; Sanmathi, Charulatha ; Bristow, Linda J. ; Park, Hyunsoo ; Subramanian, Murali ; Molski, Thaddeus ; Gupta, Grandhi V. R. K. M. ; Srikumar, Bettadapura N. ; Mathur, Arvind ; Nophsker, Michelle

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (K_i = 4.0 nM) and selective inhibition of GluN2B receptor function (IC₅₀ = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

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