- [Show abstract] [Hide abstract] ABSTRACT: In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
- [Show abstract] [Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- [Show abstract] [Hide abstract] ABSTRACT: We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
- [Show abstract] [Hide abstract] ABSTRACT: The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.
- [Show abstract] [Hide abstract] ABSTRACT: An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC50 = 2.4 nM, EC2xPT = 1.2 μM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.
- [Show abstract] [Hide abstract] ABSTRACT: The effect of inhibiting activated blood coagulation factor XIa was determined in rat models of thrombosis and hemostasis. BMS-262084 is an irreversible and selective small molecule inhibitor of factor XIa with an IC(50) of 2.8 nM against human factor XIa. BMS-262084 doubled the activated thromboplastin time in human and rat plasma at 0.14 and 2.2 microM, respectively. Consistent with factor XIa inhibition, the prothrombin time was unaffected at up to 100 microM. BMS-262084 administered as an intravenous loading plus sustaining infusion was effective against FeCl(2)-induced thrombosis in both the vena cava and carotid artery. Maximum thrombus weight reductions of 97 and 73%, respectively (P<0.05), were achieved at a pretreatment dose of 12 mg/kg+12 mg/kg/h which increased the ex vivo activated thromboplastin time to 3.0 times control. This dose level also arrested growth of venous and arterial thrombi when administered after partial thrombus formation. BMS-262084 was most potent in FeCl(2)-induced venous thrombosis, decreasing thrombus weight 38% (P<0.05) at a threshold dose of 0.2 mg/kg+0.2 mg/kg/h. In contrast, doses of up to 24 mg/kg+24 mg/kg/h had no effect on either tissue factor-induced venous thrombosis or the ex vivo prothrombin time. Doses of up to 24 mg/kg+24 mg/kg/h also did not significantly prolong bleeding time provoked by either puncture of small mesenteric blood vessels, template incision of the renal cortex, or cuticle incision. These results demonstrate that pharmacologic inhibition of factor XIa achieves antithrombotic efficacy with minimal effects on provoked bleeding.
- [Show abstract] [Hide abstract] ABSTRACT: N,N'-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.
- [Show abstract] [Hide abstract] ABSTRACT: Caprolactam urea 1, identified as a weak Factor Xa inhibitor screening hit (IC50 = 16 μM), served as the starting point for a limited parallel-synthesis driven SAR study to improve potency. Remarkably, the corresponding thiourea analog 8c (IC50 = 0.11 μM) was 145-fold more potent against Factor Xa compared to 1. In general, caprolactam analogs containing a thiourea linker were significantly more potent than their corresponding urea counterparts, and it is hypothesized that this is partly due to a conformational preference of the thiourea linkage which facilitates binding of the terminal groups of the inhibitors to the Factor Xa S1/S4 pockets. Analog 8c was selective against a panel of related serine proteases. Upon intra-duodenal administration in rats, 8c dose-dependently increased prothrombin time ex vivo, and when dosed i.v., it demonstrated efficacy in a rat model of venous thrombosis. This thiourea lead series formed the basis for follow-on investigations to discover potent drug-like Factor Xa inhibitors using the caprolactam scaffold but employing suitable thiourea surrogates.
- [Show abstract] [Hide abstract] ABSTRACT: A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered.
- [Show abstract] [Hide abstract] ABSTRACT: Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases.
- [Show abstract] [Hide abstract] ABSTRACT: The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].
- [Show abstract] [Hide abstract] ABSTRACT: A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease specificity and aqueous stability were determined. From these studies compound 2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.
- [Show abstract] [Hide abstract] ABSTRACT: The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC(50)<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.
- [Show abstract] [Hide abstract] ABSTRACT: A peptide-based structure-activity study is reported leading to the discovery of novel potent thrombin receptor antagonists. Systematic substitution of nonproteogenic amino acids for the second and third residues of the human thrombin receptor "tethered ligand" sequence (SFLLR) led to a series of agonists with enhanced potency. The most potent pentapeptide agonist identified was Ser-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2, 9 (EC50 approximately 0.04 microM for stimulation of human platelet aggregation, approximately 10-fold more potent than the natural pentapeptide). Systematic substitution of the NH2-terminal Ser in 9 with neutral hydrophobic NH2-acyl groups led to partial agonists and eventually antagonists with unprecedented potency (greater than 1000-fold increase over the previously reported antagonist 3-mercaptopropionyl-Phe-Cha-Cha-Arg-Lys-Pro-Asn-Asp-Lys-NH2). In the series of NH2-acyl tetrapeptide antagonists, N-transcinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH 2, 41 (BMS-197525), was identified as the tightest binding (IC50 approximately 8 nM) and most potent with an IC50 approximately 0.20 microM for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. Systematic single substitutions in 41 indicated that, in addition to the NH2-terminal acyl group, the side chains at the second and third positions were also responsible for important and specific receptor interactions. The p-fluoroPhe and p-guanidinoPhe residues in the second and third positions of 41 were observed to be optimal in both the agonist and antagonist series. In the case of antagonists, however, an appropriately positioned positively charged group (i.e., protonated base) at the third residue was required. In contrast, such a substitution was not required for potent agonist activity. An even more potent antagonist resulted when 41 was extended at the C-terminus by a single Arg residue giving rise to analog 90 (BMS-200261) which had an IC50 approximately 20 nM for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. When the C-terminal Arg of 90 was replaced by an Orn-(Ndelta-propionyl) residue, the resulting antagonist 91 (BMS-200661) was suitable for use in radioligand binding assays (Kd = 10-30 nM). Antagonist activity observed for selected compounds was verified through secondary assays in that these analogs prevented SFLLRNP-NH2-stimulated GTPase activity in platelet membranes and Ca2+ mobilization in cultured human smooth muscle cells and mouse fibroblasts. Furthermore, this inhibition occurred at concentrations that had no effect on thrombin catalytic activity indicating a specific activity attributable to receptor binding and not enzyme inhibition.
- [Show abstract] [Hide abstract] ABSTRACT: 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid, 1, has been described as a non-prostanoid PGI2 mimetic that demonstrates anti-thrombotic properties of long duration in animal models of thrombosis. The effects of substitution and modification of the carbon beta-to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP-induced human platelet aggregation in vitro. Potency was sensitive to both the size of the substituent and the identity of the beta-atom. The carbamates 13c-e demonstrated IC50's of 0.28-0.36 microM and were significantly more potent than the progenitor 1, IC50 = 1.2 microM. The ethyl carbamate 13c displaced [3H]-iloprost from platelet membranes in a concentration-dependent fashion that was half maximal at 20 nM, which compares with IC50's of 171 nM for 1 and 39 nM or unlabelled iloprost. Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for PGI2, identifying 13c as a partial agonist at the platelet PGI2 receptor.
- [Show abstract] [Hide abstract] ABSTRACT: The 4,5-diphenyloxazole derivatives 2-4 were previously identified as nonprostanoid prostacyclin (PGI2) mimetics. A series of derivatives of 2-4 bearing substitutents at the carbon atom α to the ozazole ring were synthesized and evaluated as inhibitors of ADP-induced aggregation of human platelets in vitro. In the unsaturated series, the α-carbethozy derivative 10a, evaluated as an equal mixture of geometrical isomers, inhibited platelet aggregation with an IC50 of 0.36 μM. Evaluation of the individual methyl ester derivatives (E)-9a and (Z)-9a revealed that (E)-9a was 10-fold more potent than (Z)-9a. In the saturated series, the α-carbomethoxy-substituted compound 12a inhibited platelet aggregation with an IC50 of 0.08 μM, 15-fold more potent than the unsubstituted prototype 2. The potency of 12a was found to be sensitive to variation of the methoxy moiety. The ethyl (12b) and isopropyl (12d) esters were less effective as were the acid 12e and a series of amides (12f-h). Other substituents introduced at this site of the pharmacophore included P(O)(OEt)2 (25), SCH3 (31a), S(O)CH3 (31b), SO2CH3 (31c), isopropyl (31d), phenyl (31f), and CH2OH (31i). However, none were significantly more potent inhibitors of platelet function than the parent compound 2. The results indicate the presence of a pocket in the PGI2 receptor protein that preferentially recognizes small, polar but uncharged substituents. The structure-activity correlates are suggestive of a hydrogen-bond interaction between a donor moiety on the PGI2 receptor and the methoxycarbonyl functionality of 12a that is sensitive to both the size of the substituent and its stereochemical presentation in this structural class of PGI2 mimetic. The ethyl ester 12b dose-dependenlly displaced [3H] iloprost from human platelet membranes and stimulated adenylate cyclase. However, the maximal stimulation was less than that recorded for iloprost, indicating that 12b functions as a partial agonist at the PGI2 receptor.
New York City, New York, United States
- • Department of Chemistry
- • Pharmaceutical Research Institute