1204331-79-2

Upstream product

• 1204331-78-1 4-(4-carboxy-2-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid benzyl ester 
• 219511-71-4 tert-butyl N-(diaminomethylidene)carbamate 
• 1204331-77-0 4-(4-methoxycarbonyl-2-trifluoromethyl-phenyl)piperidine-1-carboxylic acid benzyl ester 
• 1204331-48-5 4-(4-methoxycarbonyl-2-trifluoromethylphenyl)piperidine-1-carboxylic acid tert-butyl ester 
• 1204331-26-9 4-(4-methoxycarbonyl-2-trifluoromethylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 
• 1393368-52-9 4-piperidin-4-yl-3-trifluoromethyl-benzoic acid methyl ester hydrochloride 
• 107317-58-8 4-bromo-3-trifluoromethylbenzoic acid methyl ester 
• 161622-14-6 4-bromo-3-(trifluoromethyl)benzoic acid 
• 375853-82-0 tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate 
• 138647-49-1 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 
• 79099-07-3 N-tert-butyloxycarbonylpiperidin-4-one 

Downstream Products

• 1204329-53-2 N-{4-[1-(piperidine-3-carbonyl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204331-80-5 N-(4-piperidin-4-yl-3-trifluoromethylbenzoyl)-N'-(tert-butoxycarbonyl)guanidine 
• 1393368-53-0 N-(4-piperidin-4-yl-3-trifluoromethylbenzoyl)-N'-(tert-butoxycarbonyl)guanidine hydrochloride 
• 1204330-29-9 N-{4-[1-(4-chloro-benzoyl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204330-30-2 N-{4-[1-(3-chloro-benzoyl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204330-33-5 N-{4-[1-(2-chloro-benzoyl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204330-86-8 N-{4-[1-(biphenyl-4-carbonyl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204330-08-4 N-{4-[1-(4-oxazol-5-yl-benzoyl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204330-07-3 N-{4-[1-(3-oxazol-5-yl-benzoyl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204330-27-7 N-[4-(1-cyclopentanecarbonyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine 
• 1204330-32-4 N-{4-[1-(3-methyl-butyryl)-piperidin-4-yl]-3-trifluoromethyl-benzoyl}-guanidine 
• 1204330-35-7 N-[4-(1-butyryl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine 
• 1204331-80-5 N-(4-piperidin-4-yl-3-trifluoromethyl-benzoyl)-(N'-tert-butoxycarbonyl)-guanidine 

Relevant academic research and scientific papers

Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat

Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl- piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.

PYRROLIDINYL AND PIPERIDINYL COMPOUNDS USEFUL AS NHE-1 INHIBITORS

Disclosed are compounds of formula (I) and compositions of the present invention which are inhibitors of the sodium proton exchanger isoform-1 (NHE-I). Also disclosed are methods of using and making the same.