8 research outputs found
Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1‑(Imidazo[1,2‑<i>a</i>]pyridin-6-yl)pyridin-2(1<i>H</i>)‑one Derivatives
Aiming to discover melanin-concentrating
hormone receptor 1 (MCHR1)
antagonists with improved safety profiles, we hypothesized that the
aliphatic amine employed in most antagonists reported to date could
be removed if the bicyclic motif of the compound scaffold interacted
with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from
our compound designs, with a cutoff value of p<i>K</i><sub>a</sub> < 8, and explored aliphatic amine-free MCHR1 antagonists
in a CNS-oriented chemical space limited by four descriptors (TPSA,
ClogP, MW, and HBD count). Screening of novel bicyclic motifs with
high intrinsic binding affinity for MCHR1 identified the imidazoÂ[1,2-<i>a</i>]Âpyridine ring (represented in compounds <b>6a</b> and <b>6b</b>), and subsequent cyclization of the central
aliphatic amide linkage led to the discovery of a potent, orally bioavailable
MCHR1 antagonist 4-[(4-chlorobenzyl)Âoxy]-1-(2-cyclopropyl-3-methylimidazoÂ[1,2-<i>a</i>]Âpyridin-6-yl)Âpyridin-2Â(1<i>H</i>)-one <b>10a</b>. It exhibited low potential for hERG inhibition and phospholipidosis
induction as well as sufficient brain concentration to exert antiobesity
effects in diet-induced obese rats
Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1‑(Imidazo[1,2‑<i>a</i>]pyridin-6-yl)pyridin-2(1<i>H</i>)‑one Derivatives
Aiming to discover melanin-concentrating
hormone receptor 1 (MCHR1)
antagonists with improved safety profiles, we hypothesized that the
aliphatic amine employed in most antagonists reported to date could
be removed if the bicyclic motif of the compound scaffold interacted
with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from
our compound designs, with a cutoff value of p<i>K</i><sub>a</sub> < 8, and explored aliphatic amine-free MCHR1 antagonists
in a CNS-oriented chemical space limited by four descriptors (TPSA,
ClogP, MW, and HBD count). Screening of novel bicyclic motifs with
high intrinsic binding affinity for MCHR1 identified the imidazoÂ[1,2-<i>a</i>]Âpyridine ring (represented in compounds <b>6a</b> and <b>6b</b>), and subsequent cyclization of the central
aliphatic amide linkage led to the discovery of a potent, orally bioavailable
MCHR1 antagonist 4-[(4-chlorobenzyl)Âoxy]-1-(2-cyclopropyl-3-methylimidazoÂ[1,2-<i>a</i>]Âpyridin-6-yl)Âpyridin-2Â(1<i>H</i>)-one <b>10a</b>. It exhibited low potential for hERG inhibition and phospholipidosis
induction as well as sufficient brain concentration to exert antiobesity
effects in diet-induced obese rats
Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test
Synthesis, Structure–Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene (hERG) Associated Liabilities
Recently, we discovered 3-aminomethylquinoline derivative <b>1</b>, a selective, highly potent, centrally acting, and orally
bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited
food intake in F344 rats with diet-induced obesity (DIO). Subsequent
investigation of <b>1</b> was discontinued because <b>1</b> showed potent hERG K<sup>+</sup> channel inhibition in a patch-clamp
study. To decrease hERG K<sup>+</sup> channel inhibition, experiments
with ligand-based drug designs based on <b>1</b> and a docking
study were conducted. Replacement of the terminal <i>p</i>-fluorophenyl group with a cyclopropylmethoxy group, methyl group
introduction on the benzylic carbon at the 3-position of the quinoline
core, and employment of a [2-(acetylamino)Âethyl]Âamino group as the
amine portion eliminated hERG K<sup>+</sup> channel inhibitory activity
in a patch-clamp study, leading to the discovery of <i>N</i>-{3-[(1<i>R</i>)-1-{[2-(acetylamino)Âethyl]Âamino}Âethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)Âbenzamide <b>(</b><i><b>R</b></i><b>)-10h</b>. The compound <b>(</b><i><b>R</b></i><b>)-10h</b> showed
potent inhibitory activity against hMCHR1 and dose-dependently suppressed
food intake in a 2-day study on DIO-F344 rats. Furthermore, practical
chiral synthesis of <b>(</b><i><b>R</b></i><b>)-10h</b> was performed to determine the molecule’s absolute
configuration