Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ

Agustin Casimiro-Garcia; Gary F Filzen; Declan Flynn; Christopher F Bigge; Jing Chen; Jo Ann Davis; Danette A Dudley; Jeremy J Edmunds; Nadia Esmaeil; Andrew Geyer; Ronald J Heemstra; Mehran Jalaie; Jeffrey F Ohren; Robert Ostroski; Teresa Ellis; Robert P Schaum; Chad Stoner

doi:10.1021/jm200409s

Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ

J Med Chem. 2011 Jun 23;54(12):4219-33. doi: 10.1021/jm200409s. Epub 2011 May 26.

Authors

Agustin Casimiro-Garcia¹, Gary F Filzen, Declan Flynn, Christopher F Bigge, Jing Chen, Jo Ann Davis, Danette A Dudley, Jeremy J Edmunds, Nadia Esmaeil, Andrew Geyer, Ronald J Heemstra, Mehran Jalaie, Jeffrey F Ohren, Robert Ostroski, Teresa Ellis, Robert P Schaum, Chad Stoner

Affiliation

¹ Pfizer Global Research and Development, Groton Laboratories, Eastern Point Rd, Groton, Connecticut 06340, United States. [email protected]

PMID: 21557540
DOI: 10.1021/jm200409s

Abstract

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Administration, Oral
Angiotensin II Type 1 Receptor Blockers / chemical synthesis*
Angiotensin II Type 1 Receptor Blockers / chemistry
Angiotensin II Type 1 Receptor Blockers / pharmacology
Animals
Antihypertensive Agents / chemical synthesis*
Antihypertensive Agents / chemistry
Antihypertensive Agents / pharmacology
Biological Availability
Blood Glucose / analysis
Crystallography, X-Ray
Drug Partial Agonism
Humans
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology
Insulin Resistance
Male
Models, Molecular
PPAR gamma / agonists*
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Radioligand Assay
Rats
Rats, Inbred SHR
Stereoisomerism
Structure-Activity Relationship
Transcriptional Activation
Triglycerides / blood

Substances

3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo(4,5-b)pyridine
Angiotensin II Type 1 Receptor Blockers
Antihypertensive Agents
Blood Glucose
Hypoglycemic Agents
Imidazoles
PPAR gamma
Pyridines
Triglycerides

Associated data

PDB/3R8A