12 research outputs found
Regioselective Synthesis of 2<i>H</i>‑Indazoles Using a Mild, One-Pot Condensation–Cadogan Reductive Cyclization
An
operationally simple and efficient one-pot synthesis of 2<i>H</i>-indazoles from commercially available reagents is reported. <i>Ortho</i>-imino-nitrobenzene substrates, generated via condensation,
undergo reductive cyclization promoted by tri-<i>n</i>-butylphosophine
to afford substituted 2<i>H</i>-indazoles under mild reaction
conditions. A variety of electronically diverse <i>ortho</i>-nitrobenzÂaldehydes and anilines were examined. To further
extend the scope of the transformation, aliphatic amines were also
employed to form <i>N</i>2-alkyl indazoles selectively under
the optimized reaction conditions
Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents
The optimization
of a new class of small molecule PCSK9 mRNA translation
inhibitors is described. The potency, physicochemical properties,
and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule.
The last step in the synthesis of the congested amide center was enabled
by three different routes. Subtle structural changes yielded significant
changes in pharmacology and off-target margins. These efforts led
to the identification of <b>7l</b> and <b>7n</b> with
overall profiles suitable for in vivo evaluation. In a 14-day toxicology
study, <b>7l</b> demonstrated an improved safety profile vs
lead <b>7f</b>. We hypothesize that the improved safety profile
is related to diminished binding of <b>7l</b> to nontranslating
ribosomes and an apparent improvement in transcript selectivity due
to the lower strength of <b>7l</b> stalling of off-target proteins
Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents
The optimization
of a new class of small molecule PCSK9 mRNA translation
inhibitors is described. The potency, physicochemical properties,
and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule.
The last step in the synthesis of the congested amide center was enabled
by three different routes. Subtle structural changes yielded significant
changes in pharmacology and off-target margins. These efforts led
to the identification of <b>7l</b> and <b>7n</b> with
overall profiles suitable for in vivo evaluation. In a 14-day toxicology
study, <b>7l</b> demonstrated an improved safety profile vs
lead <b>7f</b>. We hypothesize that the improved safety profile
is related to diminished binding of <b>7l</b> to nontranslating
ribosomes and an apparent improvement in transcript selectivity due
to the lower strength of <b>7l</b> stalling of off-target proteins
Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents
The optimization
of a new class of small molecule PCSK9 mRNA translation
inhibitors is described. The potency, physicochemical properties,
and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule.
The last step in the synthesis of the congested amide center was enabled
by three different routes. Subtle structural changes yielded significant
changes in pharmacology and off-target margins. These efforts led
to the identification of <b>7l</b> and <b>7n</b> with
overall profiles suitable for in vivo evaluation. In a 14-day toxicology
study, <b>7l</b> demonstrated an improved safety profile vs
lead <b>7f</b>. We hypothesize that the improved safety profile
is related to diminished binding of <b>7l</b> to nontranslating
ribosomes and an apparent improvement in transcript selectivity due
to the lower strength of <b>7l</b> stalling of off-target proteins
Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family
Inhibition of the sodium-coupled
citrate transporter (NaCT or SLC13A5)
has been proposed as a new therapeutic approach for prevention and
treatment of metabolic diseases. In a previous report, we discovered
dicarboxylate <b>1a</b> (PF-06649298) which inhibits the transport
of citrate in in vitro and in vivo
settings via a specific interaction with NaCT. Herein, we report the
optimization of this series leading to <b>4a</b> (PF-06761281),
a more potent inhibitor with suitable in vivo pharmacokinetic profile
for assessment of in vivo pharmacodynamics. Compound <b>4a</b> was used to demonstrate dose-dependent inhibition of radioactive
[<sup>14</sup>C]Âcitrate uptake in liver and kidney in vivo, resulting
in modest reductions in plasma glucose concentrations
Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577
Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated
protein kinase
(AMPK) activators for the potential treatment of diabetic nephropathy.
Compounds <b>1</b>–<b>3</b> were scaled to supply
material for preclinical studies, and indole <b>3</b> was selected
for advancement to first-in-human clinical trials and scaled to kilogram
quantities. The progression of the synthesis strategy for these AMPK
activators is described, as routes were selected for efficient structure–activity
relationship generation and then improved for larger scales. The developed
sequences employed practical isolations of intermediates and APIs,
reproducible cross-coupling, hydrolysis, and other transformations,
and enhanced safety and purity profiles and led to the production
of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg
of <b>3</b>. Multiple polymorphs of <b>3</b> were observed,
and conditions for the reproducible formation of crystalline material
suitable for clinical development were identified
Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577
Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated
protein kinase
(AMPK) activators for the potential treatment of diabetic nephropathy.
Compounds <b>1</b>–<b>3</b> were scaled to supply
material for preclinical studies, and indole <b>3</b> was selected
for advancement to first-in-human clinical trials and scaled to kilogram
quantities. The progression of the synthesis strategy for these AMPK
activators is described, as routes were selected for efficient structure–activity
relationship generation and then improved for larger scales. The developed
sequences employed practical isolations of intermediates and APIs,
reproducible cross-coupling, hydrolysis, and other transformations,
and enhanced safety and purity profiles and led to the production
of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg
of <b>3</b>. Multiple polymorphs of <b>3</b> were observed,
and conditions for the reproducible formation of crystalline material
suitable for clinical development were identified
Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)
Optimization
of the pharmacokinetic (PK) properties of a series
of activators of adenosine monophosphate-activated protein kinase
(AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic
acid clinical candidate (<b>1</b>) were examined with the goal
of reducing glucuronidation rate and minimizing renal excretion. Compounds <b>10</b> (PF-06679142) and <b>14</b> (PF-06685249) exhibited
robust activation of AMPK in rat kidneys as well as desirable oral
absorption, low plasma clearance, and negligible renal clearance in
preclinical species. A correlation of in vivo renal clearance in rats
with in vitro uptake by human and rat renal organic anion transporters
(human OAT/rat Oat) was identified. Variation of polar functional
groups was critical to mitigate active renal clearance mediated by
the Oat3 transporter. Modification of either the 6-chloroindole core
to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted
5-(3-pyridyl) group provided improved metabolic stability while minimizing
propensity for active transport by OAT3