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Overview

Basic Info

Drug Type

Biological products

Synonyms-

Target-

Action-

Mechanism-

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus

Inactive Indication-

Originator Organization

Beijing SL Pharmaceutical Co., Ltd.

Active Organization

Beijing SL Pharmaceutical Co., Ltd.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Pacorel, Bénédicte ; Sharma, Raman ; Amewu, Richard ; Nixon, Gemma L. ; Mbekeani, Alison ; Gibbons, Peter ; Hill, Alasdair ; Hong, W. David ; Fisher, Nicholas E. ; Charoensutthivarakul, Sitthivut ; Stocks, Paul A. ; Srivastava, Abhishek ; Berry, Neil G. ; Shone, Alison E. ; O’Neill, Paul M. ; Berger, Olivier ; Ward, Stephen A. ; Pidathala, Chandrakala ; Taylor, Lee ; Leung, Suet C. ; Warman, Ashley J. ; Biagini, Giancarlo A.

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.

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