Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.
We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
Meyers
Marvin J
MJ
St. Louis Laboratories, Pfizer Global Research and Development, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA. mmeyers8@slu.edu
Arhancet
Graciela B
GB
Hockerman
Susan L
SL
Chen
Xiangyang
X
Long
Scott A
SA
Mahoney
Matthew W
MW
Rico
Joseph R
JR
Garland
Danny J
DJ
Blinn
James R
JR
Collins
Joe T
JT
Yang
Shengtian
S
Huang
Horng-Chih
HC
McGee
Kevin F
KF
Wendling
Jay M
JM
Dietz
Jessica D
JD
Payne
Maria A
MA
Homer
Bruce L
BL
Heron
Marcia I
MI
Reitz
David B
DB
Hu
Xiao
X
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D045744:Cell Line, Tumor; D002722:Chlorobenzenes; D018360:Crystallography, X-Ray; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007192:Indenes; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D008958:Models, Molecular; D008968:Molecular Conformation; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D002722:Chlorobenzenes; D007191:Indazoles; D007192:Indenes; D000451:Mineralocorticoid Receptor Antagonists; D009570:Nitriles; C552104:(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo(g)indazole-7-carboxylic acid