173864-46-5

Upstream product

• 1485-00-3 5-((E)-2-nitroethenyl)-1,3-benzodioxole 
• 2881-83-6 ethyl 4-methoxybenzoylacetate 
• 100-06-1 1-(4-methoxyphenyl)ethanone 
• 120-57-0 piperonal 
• 173864-45-4 Ethyl 2-(4-methoxybenzoyl)-3-(3.4-methylenedioxy-phenyl)-4-nitro-butanoate 

Downstream Products

• 1026676-96-9 4-Benzo[1,3]dioxol-5-yl-1-(2-isobutylamino-ethyl)-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester 
• 220584-95-2 4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-1-(2-propylamino-ethyl)-pyrrolidine-3-carboxylic acid ethyl ester 
• 195510-47-5 4-Benzo[1,3]dioxol-5-yl-1-(2-butylamino-ethyl)-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester 

Relevant academic research and scientific papers

2,4-diarylpyrrolidine-3-carboxylic acids - Potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722

We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indan ring in SB 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acids (8) have been synthesized and evaluated for binding at ETA and ETB receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC50 = 0.36 nM for inhibition of ET-1 radioligand binding at the ETA receptor, with a 1000-fold selectivity for the ETA vs the ETB receptor. It is also a potent inhibitor (IC50 = 0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-1-induced contraction of the rabbit aorta with a pA2 = 9.20. The compound has 70% oral bioavailability in rats.

Endothelin antagonists

A compound of the formula (I): or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

Endothelin antagonists

A compound of the formula (I): or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

ENDOTHELIN ANTAGONISTS

A compound of the formula (I): STR1 or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

ENDOTHELIN ANTAGONISTS

A compound of the formula (I): STR1 or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

Pyrrolidine-3-carboxylic acids as endothelin antagonists. 2. Sulfonamide-based ET(A)/ET(B) mixed antagonists

When the N,N-dialkylacetamide side chain of the highly ET(A)-selective endothelin antagonist ABT-627 (1; [2R,3R,4S]-2-(4-methoxyphenyl)-4-(1,3- benzodioxol-5-yl)-1-[[(N,N-dibutylamino)carbonyl]methyl]pyrrolidine-3- carboxylic acid; A-147627) is replaced by N,S-dialkylsulfonami-doethyl, the resultant analogs retain ET(A) affinity, but exhibit substantial ET(B) affinity as well. Structure-activity studies reveal that modifications in the length of the two alkyl groups, and in the substitution on the anisyl ring, are important in optimizing this 'balanced' antagonist profile. In particular the combination of an N-n-propyl group, an S-alkyl chain between four and six carbons in length, and a fluorine atom ortho to the aromatic OCH3 provides compounds with sub-nanomolar affinities for both receptor subtypes, and with ET(A)/ET(B) ratios close to 1. A number of these compounds also exhibit oral bioavailabilities (in rats) in the 30-50% range and have substantial plasma half-lives. The balanced receptor-binding profile of these potent and orally bioavailable compounds complements the ET(A) selectivity observed with 1.