Synthesis and characterization of an orally bioavailable small molecule agonist of the apelin receptor. (15th July 2022)

• Record Type: Journal Article
• Authors: Narayanan, Sanju; Dai, Donghua; Vyas Devambatla, Ravi Kumar; Albert, Vincent; Bruneau-Latour, Nicolas; Vasukuttan, Vineetha; Ciblat, Stephane; Rehder, Kenneth; Runyon, Scott P.; Maitra, Rangan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 66(2022)
• Publication Date: 2022-07-15
• Subjects: Apelin receptor -- APJ -- Agonist -- Pyrazole -- Cardiovascular -- Oral; ADME absorption distribution metabolism and excretion -- AcOH acetic acid -- Boc2O di-tert-butyl dicarbonate -- BuLi n-butyllithium -- BSA bovine serum albumin -- CHO-K1 chinese hamster ovary cells -- CYP cytochrome P450 -- (COCl)2 oxalyl chloride -- CH3CN acetonitrile -- CBr4 carbon tetrabromide -- CsCO3 cesium carbonate -- DCE 1, 2-dichloroethane -- DCM/CH2Cl2 dichloromethane -- DMF N, N-dimethylformamide -- DIPEA N, N-diisopropylethylamine -- DBU 1, 8-diazabicyclo[5.4.0]undec-7-ene -- DIAD diisopropyl azodicarboxylate -- EtOAc ethyl acetate -- EtOH ethanol -- Et3N triethylamine -- EDC.HCl 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride -- Et2O diethyl ether -- GPCR G protein-coupled receptor -- H2O water -- HBTU N, N, N′N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate -- HOBt 1-hydroxybenzotriazole -- HOAt 1-hydroxy-7-azabenzotriazole -- HCl hydrochloric acid -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- KOtBu potassium tert-butoxide -- K2CO3 potassium carbonate -- LiOH·H2O lithium hydroxide monohydrate -- LiHMDS lithium bis(trimethylsilyl)amide -- LiAlH4 lithium aluminium hydride -- MeOH methanol -- MTBE methyl tert-butyl ether -- MgSO4 magnesium sulfate -- N2 nitrogen -- NaBH(OAc)3 sodium triacetoxyborohydride -- NaHMDS sodium bis(trimethylsilyl) amide -- NaCNBH3 sodium cyanoborohydride -- NaH sodium hydride -- NaHSO4 sodium bisulfate -- NH4HCO3 ammonium bicarbonate -- NH4Cl ammonium chloride -- Na2S2O3 sodium thiosulfate -- NaOH sodium hydroxide -- NH4OH ammonium hydroxide -- NaHCO3 sodium bicarbonate -- Na2SO4 sodium sulfate -- NaN3 sodium azide -- Na2CO3 sodium carbonate -- NaIO4 sodium periodate -- POBr3 phosphorus (V) oxybromide -- PBS phosphate-buffered saline -- iPrOH/IPA isopropyl alcohol -- Pd(PPh3)4 tertrakis(triphenylphospine)palladium(0) -- Pd(OAc)2 palladium(II) acetate -- P(tBu)3HBF4 tri-tert-butylphosphonium tetrafluoroborate -- PBu3 tributylphosphine -- P(o-tolyl)3 tri(o-tolyl)phosphine -- PPh3 triphenyl phosphine -- SAR structure–activity relationship -- SD rats Sprague-Dawley rats -- TFA trifluorocetic acid -- TFFA trifluoroacetic anhydride -- THF tetrahydrofuran -- TBTU 2-(1H-Benzotriazole-1-yl)-1, 1, 3, 3-tetramethylaminium tetrafluoroborate -- TLC thin layer chromatography -- ZnBr2 zinc bromide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116789
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The apelin receptor (APJ) is a target for cardiovascular indications. Previously, we had identified a novel pyrazole-based agonist 1 (( S )- N -(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2, 6-dimethoxyphenyl)-1 H -pyrazole-3-carboxamide hydrochloride) of this GPCR. Systematic modification of 1 was performed to produce compounds with improved potency and ADME properties. Orally bioavailable compound 47 with favorable agonist potency (Ca 2+ EC50 = 24 nM, cAMPi EC50 = 6.5 nM) and pharmacokinetic properties (clearance ∼20 mL/min/kg in rats) was identified. This compound has vastly reduced brain penetration and is devoid of significant off-target liability. In summary, a potent and selective APJ agonist suitable for in vivo studies of APJ in peripheral tissues after oral administration has been identified.