Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.
The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.
Discovery Chemistry and Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. natesan.murugesan@bms.com
Natesan
N
Murugesan
John E
JE
Tellew
Zhengxiang
Z
Gu
Bridgette L
BL
Kunst
Leena
L
Fadnis
Lyndon A
LA
Cornelius
Rose Ann F
RA
Baska
Yifan
Y
Yang
Sophie M
SM
Beyer
Hossain
H
Monshizadegan
Kenneth E
KE
Dickinson
Balkrushna
B
Panchal
Maria T
MT
Valentine
Saeho
S
Chong
Richard A
RA
Morrison
Kenneth E
KE
Carlson
James R
JR
Powell
Suzanne
S
Moreland
Joel C
JC
Barrish
Mark C
MC
Kowala
John E
JE
Macor
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; C465457:BMS 248360; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D000804:Angiotensin II