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1.
Org Biomol Chem ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538747

RESUMO

A facile, DAST-mediated intramolecular cyclization of 3-hydroxy-3-(2-((3-methoxybenzyl)oxy)phenyl)indolin-2-one derivatives for the synthesis of spirooxindoles fused with dibenzoxepine moieties is described. The success of this reaction is highly dependent on the choice of solvent (promoted by DCM and 1,2-DCE) and the electronic nature of the pendant aromatic ring, which is favored by the presence of electron-donating substituents. The reaction is believed to proceed through an intramolecular Friedel-Crafts-type reaction. Various dibenzoxepine-fused spirooxindoles were successfully synthesized in up to 98% yield. This methodology provides libraries of structurally diverse and medicinally important small molecules that could aid in the search for new bioactive molecules.

2.
J Med Chem ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591748

RESUMO

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.

3.
J Med Chem ; 64(3): 1454-1480, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492963

RESUMO

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.

4.
J Org Chem ; 86(2): 1730-1747, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33356273

RESUMO

Indole and indoline rings are important pharmacophoric scaffolds found in marketed drugs, agrochemicals, and biologically active molecules. The [2 + 2] cycloaddition reaction is a versatile strategy for constructing architecturally interesting, sp3-rich cyclobutane-fused scaffolds with potential applications in drug discovery programs. A general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes has been realized. A substrate-based screening approach led to the discovery of tert-butyloxycarbonyl (Boc)-protected indole-2-carboxyesters as suitable motifs for the intermolecular [2 + 2] cycloaddition reaction. Significantly, the reaction proceeds in good yield with a wide variety of both activated and unactivated alkenes, including those containing free amines and alcohols, and the transformation exhibits excellent regio- and diastereoselectivity. Moreover, the scope of the indole substrate is very broad, extending to previously unexplored azaindole heterocycles that collectively afford fused cyclobutane containing scaffolds that offer unique properties with functional handles and vectors suitable for further derivatization. DFT computational studies provide insights into the mechanism of this [2 + 2] cycloaddition, which is initiated by a triplet-triplet energy transfer process. The photocatalytic reaction was successfully performed on a 100 g scale to provide the dihydroindole analog.

5.
Indian J Public Health ; 64(4): 386-392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33318390

RESUMO

Background: Each year, between 50,000 and 100,000 women worldwide develop obstetric fistulae. Approximately 2 million girls across Asia and Africa are estimated to be affected by this condition. However, there is no reliable data on its prevalence in South-East Asia region (SEAR). Objectives: The objective of this study is to systematically review and synthesize the data on the prevalence and management of obstetric fistula in SEAR. Methods: We searched for the literature that described the prevalence and management practices of obstetric fistula in SEAR. We followed the PRISMA guidelines to select the articles for the review. The quality and relevance were assessed by two reviewers independently using the SIGN checklist. A total of five articles and reports were selected for the review. To review the management practices, we found 63 original studies that were included in the review. Results: We found five community-based studies estimating the prevalence of obstetric fistula in SEAR; 3 studies were from India, one from Bangladesh and one from Nepal. The pooled prevalence according to self-reports was 1.11 (3 studies including 671,133 participants, 95% confidence interval [CI] 1.09, 1.14) per 100 women. The pooled prevalence of obstetric fistula based on the clinical examination was 0.10 (3 studies involving 4547 participants, 95% CI 0.01, 0.20) per 100 women. The value was close to the pooled estimate based on the smaller studies. Conclusion: More studies are needed to estimate reliable community-based prevalence data and also need to develop evidence-based management guidelines.

6.
J Med Chem ; 63(23): 14740-14760, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33226226

RESUMO

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.

7.
ACS Med Chem Lett ; 11(11): 2190-2194, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33214828

RESUMO

Stability of antibody-drug conjugates (ADCs) in mouse serum is one of the critical requirements for the evaluation of ADCs in mouse tumor models. Described herein is a strategy to address the mouse serum instability of uncialamycin linker-payloads through various chemical approaches that involve modification of different parts of the linker and payload. This effort ultimately led to the identification of a m-amide p-aminobenzyl carbamate (MA-PABC) group that resulted in linkers with dramatic improvement of mouse serum stability without affecting the desired proteolytic cleavage.

8.
ACS Med Chem Lett ; 11(11): 2195-2203, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33214829

RESUMO

Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

9.
J Med Chem ; 63(22): 13913-13950, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33155811

RESUMO

A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine-citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 µmol/kg).

10.
J Pharm Biomed Anal ; 192: 113651, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-33010500

RESUMO

A pure ß-​D-​Glucopyranosiduronic acid metabolite (≥98.0 % purity and a single impurity ≤0.50 %) was requested for biological studies. Due to its unusual instability, the purification of the glucuronide metabolite was extremely challenging. Initially, the crude sample (89 % HPLC area purity) was purified on a Waters SunFire C8 OBD column with 40 mM ammonium acetate buffer and acetonitrile as the mobile phase under a gradient program. The purified glucuronide metabolite solid was obtained by evaporation and lyophilization. However, this procedure yielded the target compound with 97.6 % HPLC area purity and did not meet the requirements. Through the investigation, lyophilization was identified as the key step for the purity of the metabolite, and further lyophilization resulted in an increased amount of the degraded impurities. To better understand the compound, stability studies of the purified metabolite were conducted under sample media, organic solvent, acid, base, and light exposure. The compound was observed to be extremely unstable in water, acid, base and methanol, and sensitive to light, but relatively stable in ammonium acetate buffer (pH 5.0). Taking into account compound stability and the initial purification method, the improved purification procedure was successfully developed and the purified glucuronide metabolite was obtained with 99.2 % HPLC area purity and 0.39 % of the largest single impurity.

11.
ACS Med Chem Lett ; 11(9): 1766-1772, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32944145

RESUMO

Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P1 differentiated modulators 3-6. The effects of analogs 3-6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED50 < 0.05 mg/kg) and predicted human half-life (t 1/2 ∼ 5 days).

12.
Bioorg Med Chem Lett ; 30(17): 127392, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738966

RESUMO

A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.

13.
J Org Chem ; 85(17): 11519-11530, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32786620

RESUMO

Unnatural amino acids play an important role in peptide based drug discovery. Herein, we report a class of differentially protected azatryptophan derivatives synthesized from N-tosyl-3-haloazaindoles 1 and Fmoc-protected tert-butyl iodoalanine 2 via a Negishi coupling. Through ligand screening, Pd2(dba)3/XPhos was found to be a superior catalyst for the coupling of 1 with the zinc derivative of 2 to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate derivatives 3 in 69-91% isolated yields. In addition, we have demonstrated that the protecting groups, namely, Ts, Fmoc, and tBu, can be easily removed selectively.

14.
J Org Chem ; 85(16): 10988-10993, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32687358

RESUMO

We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.

15.
ACS Med Chem Lett ; 11(6): 1221-1227, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32551004

RESUMO

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

16.
Bioorg Med Chem ; 28(13): 115541, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32389483

RESUMO

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir.

17.
J Med Chem ; 63(13): 7226-7242, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32456431

RESUMO

Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.


Assuntos
Fator XIa/antagonistas & inibidores , Fibrinolíticos/administração & dosagem , Fibrinolíticos/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Fator XIa/química , Fator XIa/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Coelhos , Relação Estrutura-Atividade
18.
IEEE Trans Neural Syst Rehabil Eng ; 28(6): 1317-1324, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32310776

RESUMO

The sit-to-stand test (STS) is a simple test of function in older people that can identify people at risk of falls. The aim of this study was to develop two novel methods of evaluating performance in the STS using a low-cost RGB camera and another an instrumented chair containing load cells in the seat of the chair to detect center of pressure movements and ground reaction forces. The two systems were compared to a Kinect and a force plate. Twenty-one younger subjects were tested when performing two 5STS movements at self-selected slow and normal speeds while 16 older fallers were tested when performing one 5STS at a self-selected pace. All methods had acceptable limits of agreement with an expert for total STS time for younger subjects and older fallers, with smaller errors observed for the chair (-0.18 ± 0.17 s) and force plate (-0.19 ± 0.79 s) than for the RGB camera (-0.30 ± 0.51 s) and the Kinect (-0.38 ± 0.50 s) for older fallers. The chair had the smallest limits of agreement compared to the expert for both younger and older participants. The new device was also able to estimate movement velocity, which could be used to estimate muscle power during the STS movement. Subsequent studies will test the device against opto-electronic systems, incorporate additional sensors, and then develop predictive equations for measures of physical function.

19.
J Biomech Eng ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32154835

RESUMO

The aim of this study was to investigate whether parameters from an instrumented one-leg stance on a force plate test could provide relevant information related to fall risk in older people. Twenty-five community dwelling older people and 25 young subjects performed a one-leg stance while standing on a force plate, with parameters related to transferring weight onto one leg and postural sway in singe-leg stance evaluated. Older participants were classified as being at risk of falling if their performance did not meet one of the previously-established cut-offs for the Five Times Sit-To-Stand and Timed-Up-and-Go tests. Eleven older participants were classified as having a risk of falls. The only significant difference between groups during the weight transfer phase was in the mediolateral displacement, with the fall risk group having less sway than the other groups, signifying a more precautionary approach. With respect to postural sway, both the younger subjects and the no fall risk group stabilised sufficiently to decrease their sway compared to initial values after four and six seconds, respectively. In contrast, the fall risk group was unable to stabilise during the one-leg stance, and continued to sway throughout the 10-sec recording period. These findings suggest that the normal one-leg stance test might not be suitable to detect fall risk. In contrast, an instrumented version of the test could provide valuable additional information that could identify risk of falling in older people.

20.
ACS Med Chem Lett ; 11(2): 172-178, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32071685

RESUMO

Novel imidazole-based TGFßR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFßR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFß-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFßR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

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