10 research outputs found
Reaction of Alkyl Halides with Rongalite: One-Pot and Telescoped Syntheses of Aliphatic Sulfonamides, Sulfonyl Fluorides, and Unsymmetrical Sulfones
An efficient methodology has been
developed for the one-pot or
telescoped synthesis of aliphatic sulfonamides, sulfonyl fluorides,
and unsymmetrical sulfones on the basis of interrupted alkylation
of sodium hydroxyÂmethylÂsulfinate (rongalite) with alkyl
halides. The protocols are conducted under mild conditions, use inexpensive
and shelf-stable reagents, and are not sensitive to air/moisture.
These conditions can be applied in rapid parallel chemical synthesis,
which was demonstrated by the preparation of a small sulfonamide library
based on the core structure of the anticoagulant drug Tirofiban
Copper-Catalyzed Synthesis of Masked (Hetero)Aryl Sulfinates
Catalysis using substoichiometric
copper facilitates the synthesis
of masked (hetero)aryl sulfinates under mild, base-free conditions
from aryl iodides and the commercial sulfonylation reagent sodium
1-methyl 3-sulfinopropanoate (SMOPS). The development of a tert-butyl ester variant of the SMOPS reagent allowed the
use of aryl bromide substrates. The sulfones thus generated can be
unmasked and functionalized in situ to form a variety of sulfonyl-containing
functional groups
Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)
Sodium-phosphate cotransporter 2a,
or NaPi2a (SLC34A1), is a solute-carrier
(SLC) transporter located in the kidney proximal tubule that reabsorbs
glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary
phosphate excretion and correct maladaptive mineral and hormonal derangements
associated with increased cardiovascular risk in chronic kidney disease–mineral
and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors
have been described. Herein, we detail the discovery of the first
series of selective NaPi2a inhibitors, resulting from optimization
of a high-throughput screening hit. The oral PK profile of inhibitor
PF-06869206 (<b>6f</b>) in rodents allows for the exploration
of the pharmacology of selective NaPi2a inhibition
Discovery and in Vitro Optimization of 3‑Sulfamoylbenzamides as ROMK Inhibitors
Inhibitors
of the renal outer medullary potassium channel (ROMK)
show promise as novel mechanism diuretics, with potentially lower
risk of diuretic-induced hypokalemia relative to current thiazide
and loop diuretics. Here, we report the identification of a novel
series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS
hit <b>4</b>, this series was optimized to provide ROMK inhibitors
with good in vitro potencies and well-balanced ADME profiles. In contrast
to previously reported small-molecule ROMK inhibitors, members of
this series were demonstrated to be highly selective for inhibition
of human over rat ROMK and to be insensitive to the N171D pore mutation
that abolishes inhibitory activity of previously reported ROMK inhibitors
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
Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)
Increased
fructose consumption and its subsequent metabolism have
been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin
resistance in humans. Since ketohexokinase (KHK) is the principal
enzyme responsible for fructose metabolism, identification of a selective
KHK inhibitor may help to further elucidate the effect of KHK inhibition
on these metabolic disorders. Until now, studies on KHK inhibition
with small molecules have been limited due to the lack of viable in
vivo pharmacological tools. Herein we report the discovery of <b>12</b>, a selective KHK inhibitor with potency and properties
suitable for evaluating KHK inhibition in rat models. Key structural
features interacting with KHK were discovered through fragment-based
screening and subsequent optimization using structure-based drug design,
and parallel medicinal chemistry led to the identification of pyridine <b>12</b>
Discovery and Preclinical Characterization of 6‑Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]‑1<i>H</i>‑indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy
Adenosine
monophosphate-activated protein kinase (AMPK) is a protein
kinase involved in maintaining energy homeostasis within cells. On
the basis of human genetic association data, AMPK activators were
pursued for the treatment of diabetic nephropathy. Identification
of an indazole amide high throughput screening (HTS) hit followed
by truncation to its minimal pharmacophore provided an indazole acid
lead compound. Optimization of the core and aryl appendage improved
oral absorption and culminated in the identification of indole acid,
PF-06409577 (<b>7</b>). Compound <b>7</b> was advanced
to first-in-human trials for the treatment of diabetic nephropathy
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
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