We report operationally facile methods for the synthesis of substituted dihydroisoquinolinones and tetrahydroisoquinolines from readily accessible o-bromobenzyl bromides and o-bromobenzaldehydes, ...respectively. While classical electrophilic aromatic substitution reactions are tailored to the construction of saturated isoquinolines derived from electron-rich precursors, we demonstrate efficient syntheses from electronically diverse substrates to produce cyclized products as single regioisomers.
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Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein ...(F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.
Transient receptor potential vanilloid 3 (TRPV3) is a Ca2+- and Na+-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ...ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.
A new structural class of histamine H4 receptor antagonists (6−14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H4 ...antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H4 antagonists, functional H4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H4 pharmacology. It is a potent H4 antagonist in functional assays across species (FLIPR Ca2+ flux, K b < 5.7 nM), has high (>190×) selectivity for H4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED50 = 37 μmol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED50 = 72 μmol/kg, rat).
A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried ...out to optimize the potency, which led to compound 3, 4-tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6-tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-ylbenzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H4R antagonists in pain.
Structure−activity relationships were investigated on the tricyclic dihydropyridine (DHP) KATP openers 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopentabnaphthalene-1,8-dione (6) ...and 10-(3-bromo-4-fluorophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (65). Substitution off the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for KATP channel activity using Ltk− cells stably transfected with the Kir6.2/SUR2B exon 17− splice variant and in an electrically stimulated pig bladder strip assay. A select group of compounds was evaluated for in vitro inhibition of spontaneous bladder contractions. Several compounds were found to have the unique characteristic of partial efficacy in both the cell-based and electrically stimulated bladder strip assays but full efficacy in inhibiting spontaneous bladder strip contractions. For compound 23b, this profile was mirrored in vivo where it was fully efficacious in inhibiting spontaneous myogenic bladder contractions but only partially able to reduce neurogenically mediated reflex bladder contractions.
A series of compounds was designed as dual inhibitors of the H3 receptor and the norepinephrine transporter. Compound 5 (rNET K i = 14 nM; rH3R K i = 37 nM) was found to be efficacious in a rat model ...of osteoarthritic pain.
A novel series of histamine H3 antagonists containing quinoline core was disclosed. Compound 51 showed 50pM affinity for human histamine H3 in the radio ligand binding assay.
A series of quinoline ...containing histamine H3 antagonists is reported herein. These analogs were synthesized via the Friedlander quinoline synthesis between an aminoaldehyde intermediate and a methyl ketone allowing for a wide diversity of substituents at the 2-position of the quinoline ring.
A new structural series of histamine H3 receptor antagonist was developed. The new compounds are based on a quinoline core, appended with a required basic aminoethyl moiety, and with potency- and ...property-modulating heterocyclic substituents. The analogs have nanomolar and subnanomolar potency for the rat and human H3R in various in vitro assays, including radioligand competition binding as well as functional tests of H3 receptor-mediated calcium mobilization and GTPγS binding. The compounds possessed favorable drug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Several compounds were found to be efficacious in animal behavioral models of cognition and attention. Further studies on the pharmaceutic properties of this series of quinolines discovered a potential problem with photochemical instability, an issue which contributed to the discontinuation of this series from further development.
Although ATP-sensitive K + channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate
native and recombinant K ATP channels have been ...less forthcoming. This study reports the identification and pharmacological characterization of a novel
iodinated 1,4-dihydropyridine K ATP channel opener, 125 IA-312110 (9R)-9-(4-fluoro-3- 125 iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano3,4- b thieno2,3- e pyridin-8(7H)-one-1,1-dioxide. Binding of 125 IA-312110 to guinea pig cardiac ( K D = 5.8 nM) and urinary bladder ( K D = 4.9 nM) membranes were of high affinity, saturable, and to a single set of binding sites. Displacement of 125 IA-312110 by structurally diverse potassium channel openers (KCOs) indicated a similar rank order of potency in both guinea
pig cardiac and bladder membranes ( K i , heart): A-312110 (4.3 nM) > N -cyano- N â²-(1,1-dimethylpropyl)- N â³-3-pyridylguanidine (P1075) > (-)- N -(2-ethoxyphenyl)- N â²-(1,2,3-trimethylpropyl)-2-nitroethene-1,1-diamine (Bay X 9228) > pinacidil > (-)-cromakalim > N -(4-benzoyl phenyl)-3,3,3-trifluro-2-hydroxy-2-methylpropionamine (ZD6169) > 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione
(ZM244085) â« diazoxide (16.7 μM). Displacement by K ATP channel blockers, the sulfonylurea glyburide, and the cyanoguanidine N -1-(3-chlorophenyl)cyclobutyl- N â²-cyano- N â³-3-pyridinyl-guanidine (PNU-99963) were biphasic in the heart but monophasic in bladder with about a 100- to 500-fold difference
in K i values between high- and low-affinity sites. Good correlations were observed between cardiac or bladder-binding affinities
of KCOs with functional activation as assessed by their respective potencies to either suppress action potential duration
(APD) in Purkinje fibers or to relax electrical field-stimulated bladder contractions. Collectively, these results demonstrate
that 125 IA-312110 binds with high affinity and has an improved activity profile compared with other radiolabeled KCOs. 125 IA-312110 is a useful tool for investigation of the molecular and functional properties of the K ATP channel complex and for the identification, in a high throughput manner, of both novel channel blockers and openers that
interact with cardiac/smooth muscle-type K ATP channels.
![[125I]A-312110, a Novel Hig...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0026-895X/small "[125I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K+ Channel Opener: Characterization and Pharmacology of Binding")