ABSTRACT
A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Azetidines/pharmacology , Indoles/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/deficiency , Animals , Azetidines/chemical synthesis , Azetidines/chemistry , Hydrogen Bonding , Indoles/chemical synthesis , Indoles/chemistry , Mice , Mice, Knockout , Molecular Structure , Rats , Receptors, Somatostatin/metabolism , StereoisomerismABSTRACT
Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energy metabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders. Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]-propyl}-piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-isobutyramide ((S)-6b) are reported. These compounds were designed to improve the pharmacokinetic properties of the high-throughput screening lead compound 1 (SNAP 7941). The MCH1 receptor antagonists 5m and (S)-6b show reasonable pharmacokinetic profiles (rat bioavailability = 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated the inhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral in vivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose = 0.3 mg/kg.
Subject(s)
Acetamides/chemical synthesis , Anilides/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cytoskeletal Proteins/antagonists & inhibitors , Piperidines/chemical synthesis , Pyrimidines/chemistry , Acetamides/pharmacokinetics , Acetamides/pharmacology , Anilides/pharmacokinetics , Anilides/pharmacology , Animals , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Anxiety/psychology , Biological Availability , Brain/metabolism , Calcium/metabolism , Cell Line , Cytoskeletal Proteins/metabolism , Drinking/drug effects , Humans , Male , Piperidines/pharmacokinetics , Piperidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Social Behavior , StereoisomerismABSTRACT
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
