Chronic
hepatitis B virus (HBV) infection is a serious public health
burden, and current therapies cannot achieve satisfactory cure rate.
There are high unmet medical needs of novel therapeutic agents with
differentiated mechanism of action (MOA) from the current standard
of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical
series, is a first-in-class highly selective and orally bioavailable
HBV inhibitor which can reduce both viral antigens and viral DNA with
a novel mechanism of action. Here we report the discovery of RG7834
from a phenotypic screening and the structure–activity relationship
(SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV
but not other DNA or RNA viruses in a virus panel screening. Both
in vitro and in vivo profiles of RG7834 are described herein, and
the data support further development of this compound as a chronic
HBV therapy.
The
rise of multidrug resistant (MDR) Gram-negative (GN) pathogens
and the decline of available antibiotics that can effectively treat
these severe infections are a major threat to modern medicine. Developing
novel antibiotics against MDR GN pathogens is particularly difficult
as compounds have to permeate the GN double membrane, which has very
different physicochemical properties, and have to circumvent a plethora
of resistance mechanisms such as multiple efflux pumps and target
modifications. The bacterial type II topoisomerases DNA gyrase (GyrA2B2) and Topoisomerase IV (ParC2E2) are highly conserved targets across all bacterial species
and validated in the clinic by the fluoroquinolones. Dual inhibitors
targeting the ATPase domains (GyrB/ParE) of type II topoisomerases
can overcome target-based fluoroquinolone resistance. However, few
ATPase inhibitors are active against GN pathogens. In this study,
we demonstrated a successful strategy to convert a 2-carboxamide substituted
azaindole chemical scaffold with only Gram-positive (GP) activity
into a novel series with also potent activity against a range of MDR
GN pathogens. By systematically fine-tuning the many physicochemical
properties, we identified lead compounds such as 17r with
a balanced profile showing potent GN activity, high aqueous solubility,
and desirable PK features. Moreover, we showed the bactericidal efficacy
of 17r using a neutropenic mouse thigh infection model.
CuI-catalyzed coupling of vinyl halides with carbazates gives N-protected N-alkenylhydrazines, which are condensed with ketones under acidic conditions to give polysubstituted pyrroles. The pyrrole synthesis may go through a similar mechanism with Fischer indole synthesis, which involves a [3,3]-sigmatropic rearrangement and other reactions.
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