Dual angiotensin II and endothelin A receptor antagonists: synthesis of 2'-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics.
In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.
Murugesan
Natesan
N
Discovery Chemistry and Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400 USA. natesan.murugesan@bms.com
Gu
Zhengxiang
Z
Fadnis
Leena
L
Tellew
John E
JE
Baska
Rose Ann F
RA
Yang
Yifan
Y
Beyer
Sophie M
SM
Monshizadegan
Hossain
H
Dickinson
Kenneth E
KE
Valentine
Maria T
MT
Humphreys
W Griffith
WG
Lan
Shih-Jung
SJ
Ewing
William R
WR
Carlson
Kenneth E
KE
Kowala
Mark C
MC
Zahler
Robert
R
Macor
John E
JE
D000284:Administration, Oral; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D000077405:Irbesartan; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology
C496400:4'-((2-butyl-4-oxo-1,3-diazaspiro(4.4)non-1-en-3-yl)methyl)-N-(4,5-dimethyl-3-isoxazolyl)-2'-(ethoxymethyl)(1,1'-biphenyl)-2-sulfonamide; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; C465457:BMS 248360; D001713:Biphenyl Compounds; D065130:Endothelin A Receptor Antagonists; D007555:Isoxazoles; D044140:Receptor, Angiotensin, Type 1; D013449:Sulfonamides; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan