Hydrochloride Salt of the GABAkine KRM-II-81

Md Yeunus Mian; Branka Divović; Dishary Sharmin; Kamal P Pandey; Lalit K Golani; V V N Phani Babu Tiruveedhula; Rok Cerne; Jodi L Smith; Xingjie Ping; Xiaoming Jin; Gregory H Imler; Jeffrey R Deschamps; Arnold Lippa; James M Cook; Miroslav M Savić; James Rowlett; Jeffrey M Witkin

doi:10.1021/acsomega.2c03029

Hydrochloride Salt of the GABAkine KRM-II-81

ACS Omega. 2022 Jul 27;7(31):27550-27559. doi: 10.1021/acsomega.2c03029. eCollection 2022 Aug 9.

Authors

Md Yeunus Mian¹, Branka Divović², Dishary Sharmin¹, Kamal P Pandey¹, Lalit K Golani¹, V V N Phani Babu Tiruveedhula¹, Rok Cerne^{3

4

5

6}, Jodi L Smith³, Xingjie Ping⁴, Xiaoming Jin⁴, Gregory H Imler⁷, Jeffrey R Deschamps⁷, Arnold Lippa⁶, James M Cook^{1

6}, Miroslav M Savić², James Rowlett⁸, Jeffrey M Witkin^{1

3

6}

Affiliations

¹ Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States.
² Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade 11000, Serbia.
³ Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana 46260, United States.
⁴ Department of Anatomy and Cell Biology, Indiana University/Purdue University, Indianapolis, Indiana 46202, United States.
⁵ Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000 Ljubljana, Slovenia.
⁶ RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey 07452, United States.
⁷ Naval Research Laboratory, Washington, District of Columbia 20375, United States.
⁸ Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi 39216, United States.

Abstract

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABA_A receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as ¹H NMR and ¹³C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation.

Abstract

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