Potent NK1 Receptor Antagonists: Synthesis and Antagonistic Activity of Various Heterocycles with an N-(3,5-Bis(trifluoromethyl)benzyl)-N-methylcarbamoyl Substituent.

Axially Chiral N-Benzyl-N,7-dimethyl-5-phenyl-1,7-naphthyridine-6-carboxamide Derivatives as Tachykinin NK1 Receptor Antagonists: Determination of the Absolute Stereochemical Requirements

“…Interestingly, the potency of the trans-rotamer ( 1 t ) is ca. 7−20-fold higher than that of the cis-rotamer ( 1 c ), indicating a conformational requirement for NK 1 receptor binding 1a. In the conformational studies on 1 t (including 1 c ) and CP-99,994, a representative NK 1 antagonist, two phenyl rings (i.e., the C (5) -phenyl and benzylic phenyl in 1 t ) and a heteroatom (i.e., nitrogen or oxygen at the carboxamide moiety in 1 t ) were well-superimposed.…”

“…We recently described the discovery of potent and orally active tachykinin NK 1 receptor antagonists, 6-( N -benzyl- N -methylcarboxamide) derivatives of pyrido[3,4- b ]pyridine (1,7-naphthyridine) (e.g., 1 t ; Figure ), by extensive structure−activity relationship (SAR) studies on a series of N -benzylcarboxamides with isoquinolone and related nuclei. Compound 1 , N -[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro- N ,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide, exists in the form of two separable isomers (rotamers), trans ( 1 t ) and cis ( 1 c ) with respect to the amide bond, which are interconverted and reach an equilibrium state of a ca.…”

Substance P: Structure, Function, and Therapeutics

“…al. [246] have proposed a role of the basic nitrogens as having an anchoring function in the phospholipid component of the membrane. Modeling studies have been performed to generate the pharmacophore.…”

“…Energy minimized structure shows structural similarity with the Xray crystal studies. N-[3,5-bis(trifluromethyl)benzyl]-Nmethylcarbamoyl heterocycles [246] have been modified at the isoquinoline and pyrido [3,4-b]pyridine moieties at ring A and B as shown in Fig. (1) and SAR of these molecules have been studied.…”

“…al. [246] have estimated conformational flexibility from the rotational barriers around the two bonds as shown in Fig. (1a), and found restricted rotation around the bond between the amide moiety and the ring A and having a high energy barrier.…”