Biphenylsulfonamide Endothelin Antagonists:  Structure−Activity Relationships of a Series of Mono- and Disubstituted Analogues and Pharmacology of the Orally Active Endothelin Antagonist 2‘-Amino-N- (3,4-dimethyl-5-isoxazolyl)-4‘-(2-methylpropyl)[1,1‘-biphenyl]-2-sulfonamide (BMS-187308)

Abstract

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

A Photostable Silicon Rhodamine Platform for Optical Voltage Sensing

“…Berkeley Red was prepared according to the same procedure described above from 3 (50 mg, 0.15 mmol, 1.0 equiv), tri-fluoromethanesulfonic anhydride (26 μL, 0.15 mmol, 1.0 equiv), 1 55 (83 mg, 0.30 mmol, 1.5 equiv) and n -BuLi (1.6 M in hexane, 0.19 mL, 0.30 mmol, 1.5 equiv). The product was obtained as a dark blue solid (6.3 mg, 0.014 mmol, 9%).…”

Benzoxaboroles – Old compounds with new applications

“…Several benzyl alcohols can be directly metalated with secbutyllithium/TMEDA [10,38] or n-butyllithium [39] to give benzoxaboroles after reaction with borate, hydrolysis and cyclization (method B3a, b). …”

“…The most important synthetic application of benzoxaboroles is their use in Suzuki-Miyaura coupling (Scheme 6) [22,24,32,[38][39][40][42][43][44][45][46][47][48][49]. In this reaction benzoxaboroles or their esters react with aryl halides to give ortho-arylsubstituted benzyl alcohols in high yield.…”

Drug Design Strategies for Targeting G-Protein-Coupled Receptors

“… GPCR privileged substructures: Examples of GPCR ligands sharing the biphenyl or diphenylmethyl ( 1 – 3 ), spiropiperidine ( 4 – 6 ), or xanthine ( 7 – 8 ) moiety are shown. 1 , Angiotensin II type‐1 antagonist (losartan); 2 , endothelin‐A antagonist (preclinical); 104 3 , histamine‐H1 antagonist (fexofenadine); 4 , neurokinin NK 2 antagonist (preclinical); 5 , monocyte chemoattractant‐1 (MCP‐1)/CCR2 antagonist; 6 , dopamine antagonist (spiperone); 7 , adenosine (A 1 ) antagonist (phase II); 8 , adenosine (A 3 ) antagonist. …”