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1.
J Med Chem ; 59(1): 194-205, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26653180

RESUMO

As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 µM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.


Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Microssomos/enzimologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Disponibilidade Biológica , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase/farmacocinética , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Cães , Descoberta de Drogas , Humanos , Microssomos/efeitos dos fármacos , Modelos Moleculares , Prostaglandina-E Sintases , Ratos , Relação Estrutura-Atividade
2.
ACS Med Chem Lett ; 5(10): 1138-42, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25313327

RESUMO

Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.

3.
Bioorg Med Chem Lett ; 17(12): 3349-53, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17434304
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