Discovery of novel phenylpyridone derivatives as potent and selective MCH1R antagonists.

The design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice.

CCR1 chemokine receptor antagonist.

The selective accumulation and activation of leukocytes in inflamed tissues contributes to the pathogenesis of inflammatory and autoimmune diseases such as infection, rheumatoid arthritis, allergic asthma, atopic dermatitis, and multiple sclerosis. A substantial body of reports suggests that chemokines and their receptors, which belong to a family of seven transmembrane G-protein coupled receptors (GPCR), may be involved in the selective accumulation and activation of leukocytes in inflamed tissues, and in the pathogenesis of inflammatory and autoimmune diseases. One such receptor is CCR1 which is a receptor for CC chemokines, such as CCL5 (RANTES) and CCL3 (MIP-1alpha). The involvement of CCR1 in immunological diseases now is documented in several preclinical studies with CCR1 deficient mice, anti-CCR1 antibodies and CCR1 antagonists, suggesting that CCR1 may be an attractive therapeutic target for a variety of diseases. Publications and patents describing CCR1 antagonists and their pharmacological effects have recently been disclosed. This review highlights the biology and pathophysiology of CCR1, and some of its currently reported antagonists. Additionally, our approach to CCR1 drug discovery is summarized.

Structure-activity relationships of 2-(benzothiazolylthio)acetamide class of CCR3 selective antagonist.

The structure activity relationships of novel selective CCR3 receptor antagonists, 2-(benzothiazolylthio)acetamimde derivatives were described. A lead structure (1a) was discovered from the screening of the focused library that was based on the structure of our dual antagonists for the human CCR1 and CCR3 receptors. Derivatization of 1a including incorporation of substituent(s) into each benzene ring of the benzothiazole and piperidine side chain resulted in the identification of potent and selective compounds (1b, r, s) exhibiting nano-molar binding affinity (IC(50)s: 1.5-3.0 nM) and greater than 800-fold selectivity for the CCR3 receptor over the CCR1 receptor.

Structure-activity relationships of xanthene carboxamides, novel CCR1 receptor antagonists.

The structure-activity relationships of xanthene carboxamide derivatives on the CCR1 receptor binding affinity and the functional antagonist activity were described. Previously, we reported a quaternarized xanthen-9-carboxamide 1 as a potent human CCR1 receptor antagonist that was derived from a xanthen-9-carboxamide lead 2a. Further derivatization of 2a focusing on installing an additional substituent into the xanthene ring resulted in the identification of 2b-1 with IC(50) values of 1.8nM and 13nM in the binding assay using human CCR1 receptors transfected CHO cells and in the functional assay using U937 cells expressing human CCR1 receptors, respectively.

A convenient synthetic method of a 5,7-diarylcyclopenteno-[1,2-b]pyridine-6-carboxylate: a key intermediate for potent endothelin receptor antagonists.

A convenient method for the synthesis of the title intermediate 4 was described. The key steps of this synthesis involved: (1) regioselective addition reaction of arylzinc reagent to quinolic anhydride in 42% isolated yield, (2) conversion of a ketoacid to an enone, which was achieved in 65% yield by intramolecular Knoevenagel reaction of beta-ketoester generated by condensation of an acid imidazolide with an ester enolate, followed by dehydration assisted with silica gel, and (3) stereoselective reduction of an allyl alcohol in 75% yield with zinc under acidic conditions. This synthesis enabled us to provide hundreds of grams of without chromatographic purification.

6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.

Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model.