RESUMO
Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.
Assuntos
Metaloproteases/metabolismo , Inibidores de Proteases/farmacologia , Albumina Sérica Humana/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Animais , Proteína Morfogenética Óssea 1/metabolismo , Meia-Vida , Humanos , Camundongos , Estudo de Prova de Conceito , Inibidores de Proteases/farmacocinéticaRESUMO
Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Canais de Cátion TRPC/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Diglicerídeos/metabolismo , Descoberta de Drogas , Células HEK293 , Humanos , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6RESUMO
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
Assuntos
Pirrolidinas/química , Receptores de Progesterona/agonistas , Animais , Sítios de Ligação , Carbamatos/química , Cristalografia por Raios X , Canal de Potássio ERG1 , Endometriose/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Humanos , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Receptores de Progesterona/metabolismo , Sulfonamidas/químicaRESUMO
A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXRalpha will be disclosed.
Assuntos
Proteínas de Ligação a DNA/agonistas , Indóis/síntese química , Indóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Administração Oral , Animais , Colesterol/análise , Técnicas de Química Combinatória , Cristalografia por Raios X , Indóis/química , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Camundongos , Conformação Molecular , Estrutura Molecular , Receptores Nucleares Órfãos , Ratos , Relação Estrutura-AtividadeRESUMO
Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.
Assuntos
Pirrolidinas/química , Receptores de Progesterona/agonistas , Administração Oral , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Modelos Animais , Estrutura Terciária de Proteína , Pirrolidinas/administração & dosagem , Pirrolidinas/síntese química , Ratos , Receptores de Progesterona/metabolismoRESUMO
Two classes of amino acid-derived heterocyclic progesterone receptor ligands were developed to address the metabolic issues posed by the dimethyl amide functionality of the lead compound (1). The tetrazole-derived ligands behaved as potent partial agonists, while the 1,2,4-triazole ligands behaved as potent full agonists.
Assuntos
Receptores de Progesterona/agonistas , Tetrazóis/síntese química , Aminoácidos/química , Animais , Ratos , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition.
Assuntos
Pirrolidinonas/química , Receptores de Progesterona/agonistas , Administração Oral , Animais , Sítios de Ligação , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Pirrolidinonas/síntese química , Pirrolidinonas/farmacocinética , Ratos , Receptores de Progesterona/metabolismo , Relação Estrutura-AtividadeRESUMO
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Glucocorticoides/química , Ácido Glucurônico/química , Proteínas Imediatamente Precoces/química , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Inibidores de Proteínas Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Ratos , Relação Estrutura-AtividadeRESUMO
[reaction: see text] A synthesis of the 6-aza[3.2.1]bicyclooctene (-)-2 has been completed by a short sequence of reactions that required only six operations from (S)-malic acid and featured a novel ring-closing metathesis to form the bridged bicyclic ring. Because 2 was previously converted into (-)-peduncularine (1), its preparation constitutes a formal enantioselective synthesis of 1.
Assuntos
Alcaloides/síntese química , Indóis/síntese química , Compostos Aza/síntese química , Compostos Bicíclicos com Pontes/síntese química , Alcaloides Indólicos , Malatos/química , Estrutura Molecular , EstereoisomerismoRESUMO
The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.