title: 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.
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.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Eastern Point Rd, Groton, Connecticut 06340, United States. agustin.casimiro-garcia@pfizer.com
authors.forename: Agustin
authors.initials: A
authors.lastname: Casimiro-Garcia
authors.forename: Gary F
authors.initials: GF
authors.lastname: Filzen
authors.forename: Declan
authors.initials: D
authors.lastname: Flynn
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bigge
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Davis
authors.forename: Danette A
authors.initials: DA
authors.lastname: Dudley
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
authors.forename: Nadia
authors.initials: N
authors.lastname: Esmaeil
authors.forename: Andrew
authors.initials: A
authors.lastname: Geyer
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Heemstra
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Ohren
authors.forename: Robert
authors.initials: R
authors.lastname: Ostroski
authors.forename: Teresa
authors.initials: T
authors.lastname: Ellis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schaum
authors.forename: Chad
authors.initials: C
authors.lastname: Stoner
mesh_terms: D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D018360:Crystallography, X-Ray; D054333:Drug Partial Agonism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014280:Triglycerides / Q000097:blood
chemical_list: C561058:3-(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; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D047495:PPAR gamma; D011725:Pyridines; D014280:Triglycerides