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>_a < 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 imidazo­[1,2-<i>a</i>]­pyridine 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)­oxy]-1-(2-cyclopropyl-3-methylimidazo­[1,2-<i>a</i>]­pyridin-6-yl)­pyridin-2­(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>_a < 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 imidazo­[1,2-<i>a</i>]­pyridine 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)­oxy]-1-(2-cyclopropyl-3-methylimidazo­[1,2-<i>a</i>]­pyridin-6-yl)­pyridin-2­(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

Structure-Based Design and Synthesis of 3‑Amino-1,5-dihydro‑4<i>H</i>‑pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors

We report herein the discovery and optimization of 3-amino-1,5-dihydro-4<i>H</i>-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1–3 provided aminoindazole derivative <b>1</b> as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4<i>H</i>-pyrazolopyridin-4-one derivative <b>3</b> as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of <b>20</b>. Compound <b>20</b> inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, <b>20</b> showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor