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1.
J Org Chem ; 88(18): 13135-13141, 2023 Sep 15.
Article in English | MEDLINE | ID: mdl-37657122

ABSTRACT

A one-step transformation to produce 8,9-dihydrocannabidiol (H2CBD) and related "neocannabinoids" via controlled Friedel-Crafts reactions is reported. Experimental and computational studies probing the mechanism of neocannabinoid synthesis from cyclic allylic alcohol and substituted resorcinol reaction partners provide understanding of the kinetic and thermodynamic factors driving regioselectivity for the reaction. Herein, we present the reaction scope for neocannabinoid synthesis including the production of both normal and abnormal isomers under both kinetic and thermodynamic control. Discovery and optimization of this one-step protocol between various allylic alcohols and resorcinol derivatives are discussed and supported with density functional theory calculations.

2.
Bioorg Med Chem Lett ; 22(8): 2943-7, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22424974

ABSTRACT

New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall.


Subject(s)
Amides/chemical synthesis , Drug Discovery , Piperidines/chemical synthesis , Receptor, Cholecystokinin A/agonists , Amides/chemistry , Amides/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Obese , Piperidines/chemistry , Piperidines/pharmacology , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Weight Loss/drug effects
3.
Bioorg Med Chem Lett ; 12(2): 137-40, 2002 Jan 21.
Article in English | MEDLINE | ID: mdl-11755339

ABSTRACT

A series of N-benzylpyroglutamyl-L-phenylalanine derivatives bearing carbamoyl substituents in the 3- or 4-positions was prepared and assayed for inhibition of the interaction between VCAM and VLA-4. Potent inhibition was observed in a number of analogues with substitution in the 4-position favored over the 3-position. A crystal structure of the key intermediate 25 indicates that it accesses a low energy conformation which closely matches key pharmacophores of a structurally characterized cyclic peptide.


Subject(s)
Integrins/antagonists & inhibitors , Molecular Mimicry , Peptides, Cyclic/chemistry , Phenylalanine/analogs & derivatives , Receptors, Lymphocyte Homing/antagonists & inhibitors , Cell Line , Integrin alpha4beta1 , Models, Molecular , Peptides, Cyclic/pharmacology , Phenylalanine/chemistry , Phenylalanine/pharmacology , Structure-Activity Relationship
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