3 research outputs found
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