A Novel Class of Orally Active Non-Peptide Bradykinin B2

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J. Med. Chem. 1998, 41, 4062-4079

A Novel Class of Orally Active Non-Peptide Bradykinin B2 Receptor Antagonists. 3. Discovering Bioisosteres of the Imidazo[1,2-a]pyridine Moiety Yoshito Abe,† Hiroshi Kayakiri,*,† Shigeki Satoh,† Takayuki Inoue,† Yuki Sawada,† Noriaki Inamura,‡ Masayuki Asano,§ Ichiro Aramori,| Chie Hatori,§ Hiroe Sawai,§ Teruo Oku,† and Hirokazu Tanaka⊥ Exploratory Research Laboratories, Fujisawa Pharmaceutical Company, Ltd., 5-2-3, Tokodai, Tsukuba, Ibaraki 300-2698, Japan Received May 13, 1998

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (FR167344). With this potent new lead compound in hand, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-a]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization of these new heteroaromatic derivatives revealed the detailed structure-activity relationships (SAR) around the imidazo[1,2-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50’s of 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on the pyridine moiety led to a novel pharmacophore and resulted in the identification of 99 (FR184280), whose IC50 value for human B2 receptors (0.51 nM) was comparable to that of the second-generation peptide B2 antagonist Icatibant. Introduction Bradykinin (BK), an endogenous nonapeptide, has been implicated in a variety of pathophysiological responses, including pain, inflammation, asthma, rhinitis, and hypotension.1-8 Classification of BK receptors into B1 and B2 receptors is widely accepted, and they have been identified by molecular cloning and pharmacological means.1,4,9-11 B2 receptors are expressed constitutively in many tissues and are thought to mediate most of the biological actions of BK.1,9 Since the discovery of the first BK B2 receptor antagonist by Vavrek and Stewart in 1985,12 a number of peptide B2 antagonists have been developed,13-17 including the clinically evaluated second-generation antagonists Icatibant (Hoe140)13,14 and Bradycor (CP0127).15 Despite their highly potent B2 antagonistic activity, therapeutic use is still limited because of their peptidic nature. On the other hand, few non-peptide antagonists have been disclosed.18-20 However, until our work21 there had been no reports of potent orally active non-peptide B2 antagonists. Recently, we reported the identification of a series of 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridines as the first †

Department of Medicinal Chemistry. § Department of Pharmacology. | Molecular Biological Research Laboratory. ‡ Present address: Exploratory Clinical Research, Development Division, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. ⊥ Present address: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 5328514, Japan.

orally active non-peptide BK B2 receptor antagonists 1-3 (Chart 1).21 Although their affinities for B2 receptors in human A-431 cells (human epidermoid carcinoma) were found to be very low, the discovery of a novel key pharmacophore enabled us to overcome the species difference and to identify the first clinical candidate 4a (FR167344).22,23 In the present study we explored replacement of the imidazo[1,2-a]pyridine moiety, which has been incorporated in all of our B2 antagonists, with the aim of further refinement of the basic framework and discovered several promising bioisosteres. Extensive optimization of these new heteroaromatic derivatives led us to identify three series of potent novel B2 antagonists, with nanomolar IC50’s for the human recombinant B2 receptors expressed in CHO cells.22b In particular, the quinoline series afforded the second clinical candidate, 87b (FR173657),22b,24 with excellent in vivo pharmacological profiles and a subnanomolar B2 antagonist, 99 (FR184280), with a novel pharmacophore. Herein we wish to describe the structureactivity relationships (SAR) revealed on the way to the discovery of 87b and 99. Chemistry The compounds described in this study are shown in Tables 1-5, and their synthetic methods are outlined in Schemes 1-8. Schemes 1-5 show the synthetic routes for the various heteroaromatic alcohols, which were introduced to the basic framework in place of the imidazo[1,2-a]pyridin-8-ol moiety. Synthesis of 1,2-disubstituted-4hydroxy-1H-benzimidazole derivatives was accomplished

S0022-2623(98)00300-8 CCC: $15.00 © 1998 American Chemical Society Published on Web 09/19/1998

Novel Non-Peptide BK B2 Receptor Antagonists. 3

Journal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4063

Scheme 1a

a (a) DPPA, Et N, benzene then EtOH; (b) LAH, THF; (c) AcOH, 4 N HCl; (d) BBr , CH Cl ; (e) BnBr, K CO , DMF; (f) 1 N NaOH, 3 3 2 2 2 3 EtOH; (g) DPPA, Et3N, benzene then t-BuOH; (h) R1I, NaH, DMF; (i) 4 N HCl-AcOEt; (j) R2COCl, PhNMe2; (k) Fe, AcOH, EtOH; (l) H2, Pd-C; (m) N2H4‚H2O, FeCl3‚6H2O, C, aqueous MeOH; (n) CR4, AcOH; (o) MeNCS, THF then MeI, MeCN; (p) MeCH(OH)CO2H, 4 N HCl; (q) MeI, NaH, DMF; (r) MnO2, CH2Cl2; (s) 50b, NaH, DMF; (t) 1,1′-thiocarbonylimidazole, THF; (u) MeI, K2CO3, DMF.

in the following way (Scheme 1). 3-Methoxy-2-nitrobenzoic acid (5) was converted to the carbamate 6 by Curtius rearrangement in the presence of diphenyl phosphorazidate (DPPA), triethylamine, and EtOH. Reduction of both the ethyl carbamate and the nitro groups of 6 with lithium aluminum hydride gave the diamine 7, which was cyclized with AcOH in 4 N hydrochloric acid followed by removal of the O-methyl group with boron tribromide to afford the 1,2-dimethylbenzimidazole 9. Next, introduction of various substituents at the 2-position of the benzimidazole ring was investigated. Protection of 3-hydroxy-2-nitrobenzoic acid (10) with benzyl bromide in the presence of potassium carbonate, alkaline hydrolysis of the benzyl ester 11, and subsequent Curtius rearrangement with DPPA and t-BuOH furnished the N-Boc derivative 13. Alkylation of 13 with methyl iodide or ethyl iodide using

sodium hydride as a base gave 14a,b. After removal of the N-Boc group of 14a,b, the amino group of 15a,b could be coupled with various acid chlorides smoothly to afford the amides 16a-e. Reductive cyclization of 16a-e with iron followed by catalytic deprotection of the benzyl group provided the 4-hydroxybenzimidazoles 18a-e. The diamine 19 was prepared by reduction of the nitro group of 15a with hydrazine monohydrate, iron(II) chloride hexahydrate, and carbon in aqueous MeOH. Cyclization of 19 with appropriate orthoesters and subsequent hydrogenolysis gave the 2-alkoxybenzimidazole derivatives 21a,b. Reaction of 19 with methyl isothiocyanate followed by treatment with methyl iodide in MeCN furnished the expected 2-methylamino analogue 20c, which could be alkylated to the dimethylamine 20d with methyl iodide and sodium hydride in DMF. The 2-amino derivatives 20c,d were

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Journal of Medicinal Chemistry, 1998, Vol. 41, No. 21

Abe et al.

Chart 1

Scheme 2a

Scheme 5a

a (a) Concentrated H SO , 50% fuming H SO ; (b) KOH, NaOH, 2 4 2 4 210 °C.

Scheme 3a

a (a) Dowtherm, 250 °C; (b) PhNMe , POCl , 60 °C; (c) H , Pd2 3 2 C, Et3N, AcOEt; (d) BBr3, CH2Cl2.

a (a) MeCOCl, DMAP, Et N, DMF then (NH ) CO; (b) PhNMe , 3 4 2 2 POCl3, 60 °C; (c) H2, Pd-C, Et3N, AcOEt; (d) BBr3, CH2Cl2.

Scheme 4a

a

(a) AcCHO, 2 M AcOH, 4 M AcONa, 60 °C.

deprotected to provide 21c,d. The 2-acetyl derivative 21f was prepared by cyclization of 19 with lactic acid in 4 N HCl followed by oxidation and deprotection. Hydrogenation of 15a, alkylation of the phenol 22 with the benzyl chloride 50b in the presence of sodium hydride, and subsequent cyclization with 1,1′-thiocar-

bonylimidazole gave the 2-mercapto derivative 24. The thiol group of 24 was methylated with methyl iodide using potassium carbonate as a base to afford the 2-methylthio derivative 52k. 5-Hydroxy-3-methylisoquinoline (27) was prepared by sulfonation at the 5-position of 3-methylisoquinoline (25), followed by alkaline fusion (Scheme 2).25 Synthesis of 8-hydroxy-2-methylquinazoline (32) is shown in Scheme 3. Cyclization of 2-amino-3-methoxybenzoic acid (28) with acetyl chloride in the presence of 4-(dimethylamino)pyridine and triethylamine in DMF followed by treatment with ammonium carbonate furnished the quinazolone derivative 29. Reaction of 29 with phosphorus oxychloride and subsequent catalytic hydrogenation gave the quinazoline 31, which was deprotected by treatment with boron tribromide to afford 32. Cyclization of 2,3-diaminophenol (33) with pyruvic aldehyde provided a ca. 1:1 mixture of 2- and 3-methylquinoxaline derivatives 34a,b, which were separated by silica gel column chromatography (Scheme 4). The structural assignments of these isomers were based on the X-ray crystallography of 2-methyl isomer 34a. Synthesis of 7-hydroxy-2-methylquinoline (38) is shown in Scheme 5. The crotonate 35, which was prepared by



Scheme 6a

a (a) Ac O, DMAP; (b) Cu(NO ) ‚3H O, Ac O; (c) 1 N NaOH, MeOH; (d) TBDPSCl, imidazole, DMF; (e) N H ‚H O, FeCl ‚6H O, C, 2 3 2 2 2 2 4 2 3 2 aqueous MeOH; (f) N-phthaloylglycyl chloride, pyridine, DMF; (g) MeI, NaH, DMF; (h) N2H4‚H2O, EtOH; (i) (E)-4-(N-methylcarbamoyl)cinnamic acid or (E)-3-(6-acetamidopyridin-3-yl)acrylic acid, WSCD‚HCl, HOBt, DMF; (j) n-Bu4NF, THF; (k) PPh3, CBr4, CH2Cl2; (l) MsCl, Et3N, DMF; (m) heterocyclic alcohols (BI-H, QX-H, Q-H), NaH, DMF; (n) HCl-MeOH.

Scheme 7a

a (a) n-Bu NF, THF; (b) MsCl, Et N, CH Cl ; (c) heterocyclic alcohols (BI-H, QX-H, Q-H), NaH, DMF; (d) N H ‚H O, EtOH; (e) (E)4 3 2 2 2 4 2 cinnamoyl chloride, Et3N, CH2Cl2; (f) substituted acrylic acids, WSCD‚HCl, HOBt, DMF; (g) HCl-MeOH; (h) 4-PyCOCl‚HCl, Et3N, CH2Cl2; (i) 1 N NaOH, EtOH; (j) MeNH2‚HCl, WSCD, HOBt, DMF; (k) 2-, 3-, 4-PyNH2 or PhNH2, WSCD‚HCl, HOBt, DMF.

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Scheme 8a

a (a) Ac O, AcOH; (b) LAH, THF; (c) SO ‚Py, DMSO, CH Cl ; 2 3 2 2 (d) Ph3PdCHCO2Me, THF; (e) 1 N NaOH, MeOH.

condensing m-anisidine with ethyl acetoacetate in benzene with a catalytic amount of AcOH, was cyclized in Dowtherm at 250 °C to give a 2:7 mixture of 5- and 7-methoxy-2-methyl-4-quinolones. The mixture was treated with phosphorus oxychloride followed by silica gel column separation to give 4-chloro-5-methoxy-2methylquinoline (36a) and 4-chloro-7-methoxy-2-methylquinoline (36b), respectively. Catalytic hydrogenation of 36b followed by deprotection with boron tribromide yielded the 7-quinolinol 38. Introduction of various heteroaromatic rings in place of the imidazo[1,2-a]pyridine ring onto the basic framework is shown in Scheme 6. Protection of 2,4-dichloro3-nitrobenzyl alcohol (42a)21 with the silyl group followed by reduction of the nitro group with hydrazine monohydrate, iron(III) chloride hexahydrate, and carbon gave the aniline 44a. The N-phthaloylglycinamide 45a was obtained from 44a by coupling with N-phthaloylglycyl chloride in the presence of pyridine in DMF. Alkylation of 45a with methyl iodide and sodium hydride yielded 46a. The N-phthaloyl group was deprotected with hydrazine monohydrate, and the resulting amine 47a was condensed with (E)-4-(N-methylcarbamoyl)cinnamic acid23 to give the cinnamamide 48a. Removal of the silyl protecting group with tetra-nbutylammonium fluoride and subsequent treatment with triphenylphosphine and carbon tetrabromide in CH2Cl2 provided the benzyl bromide 50a. Coupling of 50a with various heteroaromatic alcohols was performed with sodium hydride as a base to give 51, 52ae, 53, 55, 56, 58-61, 62a, and 63a, respectively. The hydrochlorides 54a, 57a, and 64c were obtained by treatment of 62a, 63a, and 52c with 10% hydrogen chloride in MeOH. Acetylation of 2,6-dimethylbenzyl alcohol (39) and selective nitration at the 3-position with copper(II) nitrate followed by hydrolysis gave the 3-nitrobenzyl alcohol derivative 42b. Subsequent silylation, reduction, coupling, and methylation provided the Nphthaloylglycinamide derivative 46b. Treatment of 46b with hydrazine monohydrate and coupling with (E)-4(N-methylcarbamoyl)cinnamic acid23 or (E)-3-(6-acetamidopyridin-3-yl)acrylic acid23 gave the cinnamamides 48b,c, which were deprotected with fluoride to yield the benzyl alcohols 49b,c. Reaction with methanesulfonyl chloride and coupling with the substituted benzimidazolols 18c,d and 21a-d,f, quinoxalinol 34a, and 2-methyl-8-quinolinol afforded 52f-j,l,m, 62b, 63b, and 73b,

Abe et al.

respectively. The quinoline derivative 62b was converted to the hydrochloride 54b. Modifications of the terminal cinnamamide and pyridyl acrylamide moiety of benzimidazoles, quinoxalines, and quinolines are shown in Scheme 7. Deprotection of the silyl moiety of the N-phthaloylglycinamides 46a,b with tetra-n-butylammonium fluoride and subsequent treatment with methanesulfonyl chloride followed by coupling with benzimidazolol 21a, quinoxalinol 34a, and 2-methyl-8-quinolinol gave 66, 67a,b, and 68a,b, respectively. Removal of the N-phthaloyl group of 66, 67a,b, and 68a,b with hydrazine monohydrate and coupling with (E)-cinnamoyl chloride, (E)-3- or 4-(substituted)cinnamic acids,23 or (E)-3-[6-(substituted)pyridin-3-yl]acrylic acids23 afforded the corresponding cinnamamides 72, 74a,b, 75a,b, 80a, 82a,d, 85, 87a, and 89a,b and the pyridyl acrylamides 73a, 77a,b, 78, 80b, 82b,c, 87b,c, 89c,d, 96, and 99, respectively. The amine 96 was acylated with isonicotinoyl chloride to give the amide 97. The esters 78 and 82a-d were hydrolyzed and condensed with the corresponding amines to afford the amides 62c,d, 63c, 84, 91, 92a-c, and 94, respectively. The quinoxaline 77a and the quinoline derivatives 62c,d, 80a,b, 85, 87a,c, 89a-d, 92b,c, 94, and 97 were treated with 10% hydrogen chloride in MeOH to give the corresponding hydrochlorides 54c,d, 76a, 81a,b, 86, 88a,c, 90a-d, 93b,c, 95, and 98, respectively. Preparation of the acrylic acid 106, which was coupled with 71a to synthesize 99 in Scheme 7, is shown in Scheme 8. Condensation of methyl 6-methylnicotinate (100) with 4-pyridinecarboxaldehyde (101) gave the (E)vinylenedipyridine 102. Reduction of the ester group of 102 with lithium aluminum hydride followed by oxidation with sulfur trioxide pyridine complex in DMSO and CH2Cl2 afforded the aldehyde 104. Wittig reaction of 104 and methyl (triphenylphosphoranylidene)acetate afforded the ester 105, which was hydrolyzed to give the acid 106. Synthesis of the other acrylic acids employed in Schemes 6 and 7 was previously described.23 Pharmacology All compounds were tested for inhibition of the specific binding of [3H]BK to B2 receptors in guinea pig ileum membrane preparations as previously reported,21-23,24a and they were also evaluated for inhibition of the specific binding of [3H]BK to B2 receptors in human A-431 cells23 or human recombinant B2 receptors expressed in CHO cells.22b Compounds having potent binding affinities were then tested for in vivo functional antagonistic activity in inhibiting BKinduced bronchoconstriction in guinea pigs by oral administration.21,22a,23,24a Results and Discussion Recently we reported the first series of orally active non-peptide BK B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton as the basic framework.21 The representative lead compounds 1-3 inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations with nanomolar IC50’s and also displayed dose-dependent in



vivo functional antagonistic activities against BKinduced bronchoconstriction in guinea pigs from 1 mg/ kg by oral administration. However, it was revealed that our non-peptide B2 antagonists showed only weak binding affinities in the human A-431 cell system. Intensive modifications of the terminal substituents at the glycine moiety allowed us to discover a novel key pharmacophore to overcome this species difference, namely, the (E)-4-(substituted)cinnamamide and (E)-3[6-(substituted)pyridin-3-yl]acrylic acid moieties, leading to the discovery of the first clinical candidate 4a.22,23 Using 4a as a new lead compound, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-a]pyridine moiety, which has been incorporated in all our B2 antagonists, with other heteroaromatic rings. To reconfirm the B2 binding affinity for human receptors, we introduced a new binding assay system with recombinant human B2 receptors expressed in CHO cells.22b Table 1 summarizes the results, indicating that the representative imidazo[1,2-a]pyridine derivatives 4a,b also exhibited potent activities in this system, with nanomolar IC50’s, and that the binding affinities for both types of human B2 receptors are consistent in a wide range of compounds. In the 5-6 condensed-ring systems, benzimidazole derivative 52a retained a 7-fold weaker binding affinity to human recombinant B2 receptors compared with imidazo[1,2-a]pyridine 4b. However, benzoxazole (51) and benzofuan (53) derivatives showed a remarkable decrease in the activity. On the other hand, in the 6-6 condensed-ring systems, the quinoline ring (54a) afforded a 8-fold increase in affinity for human recombinant B2 receptors with an IC50 value of 1.1 nM. This promising result prompted us to further investigate the quinoline and related heteroaromatic derivatives. Transposition of the nitrogen atom from the 1-position to the 3-position within the quinoline ring gave the inactive isoquinoline 55. Introduction of another nitrogen atom at the 3-position provided the quinazoline 56 which displayed a 50-fold decreased binding activity in the human recombinant system. In contrast, incorporation of a second nitrogen atom at the 4-position led to quinoxaline derivative 57a which retained good activity. However, the 3-methyl derivative 58 was 558-fold less potent than the 2-methyl derivative 57a, suggesting that the 2-methyl group interacts with the hydrophobic pocket of the B2 receptor consistent with our previously discussed hypothesis.21 Shifting the benzyloxy moiety from the 8-position to the 7-position (59) resulted in complete loss of B2 binding affinity. These results indicate that, according to the numbering of the imidazo[1,2-a]pyridine ring, the 1-nitrogen atom makes an essential electrostatic interaction with B2 receptors, while the 4-nitrogen atom is unnecessary. Moreover, the 3-substituent, which increases the affinity in the 5-6 condensed ring systems, is not necessary in the 6-6 condensed-ring systems. Replacement of the condensedring with the monocyclic rings (60, 61) resulted in a significant loss of binding activity. Thus we selected benzimidazole 52a, quinoline 54a, and quinoxaline 57a as new lead compounds for further chemical modifications. Table 2 shows the effects of modifications in the benzimidazole series on their B2 binding activities.

Enlargement of the 1-methyl group of 52a to an ethyl group (52b) slightly increased the affinity for human recombinant B2 receptors. The same enlargement at the 2-position of 52a (64c) provided 3-fold potentiation. It was remarkable that replacement of the 2-methyl group of 52a with a methoxy group (52e) afforded a 30-fold increase in human recombinant B2 affinity, while larger substituents, ethoxy (52g), methoxymethyl (52h), and ethoxycarbonylmethyl (52i) groups, resulted in a severe loss of activity. Furthermore, the 2,6-dichlorophenyl group of 52e could be replaced by the 2,6-dimethylphenyl group (52f) with only a slight loss of binding affinity and improved in vivo activity after oral administration. Substitution of the methoxy group of 52f with an electron-withdrawing acetyl group (52j) decreased the binding affinity much more severely for guinea pig ileum B2 receptors than for human recombinant B2 receptors. Replacement of the oxygen atom of the methoxy group with other heteroatoms gave much less potent compounds: i.e., the sulfide derivative 52k and the amino derivatives 52l,m. It has thus been revealed that the substituents on the imidazo[1,2-a]pyridine21 and benzimidazole rings make important contributions to binding to B2 receptors. It is interesting that the optimum combinations of substituents on both rings have similar steric requirements, even though they have different electrostatic features. With the potent benzimidazole B2 antagonists 52e,f (with nanomolar IC50’s) in hand, we next investigated improvement of their in vivo activities by modifying the terminal phenyl moiety (Table 3). N-Methylation of the methylcarbamoyl group of 52e (72) afforded a remarkable increase in inhibitory activity against BK-induced bronchoconstriction, while the binding affinity for human recombinant B2 receptors was diminished. Replacement of the N-methylcarbamoylphenyl moiety of 52e,f with the acetamidopyridyl group (73a,b) significantly improved in vivo B2 antagonistic activity again, retaining potent binding affinities for both human and guinea pig B2 receptors. In particular, compound 73b when dosed orally at 0.32 mg/kg inhibited BK-induced bronchoconstriction with an inhibitory value of 75.2%. As shown in Table 4, we attempted to optimize quinoxaline derivatives by introducing several combinations of R1, R2, and X which had been proven to afford potent binding affinities for human recombinant B2 receptors in the imidazo[1,2-a]pyridine and benzimidazole series. However, most of the quinoxaline derivatives suffered from a more severe specific difference than the former series. They did not exhibit potent binding affinities for human recombinant B2 receptors, except for 57a and 76a, which failed to show significant in vivo antagonistic activities at 1 mg/kg po. This trend was also observed in the quinazoline series (data not shown). The results indicate that introduction of the additional nitrogen atom at the 3- or 4-position within the quinoline ring is unfavorable for in vitro B2 binding affinity and in vivo antagonistic activity. Table 5 shows optimization of the quinoline series. Consistent with the previous study on the imidazo[1,2a]pyridine series, 81a,b, which do not possess a carbamoyl or amide substituent on the terminal aromatic ring, showed much lower binding affinities for human recombinant B2 receptors compared with those for

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Table 1. Replacement of the Imidazo[1,2-a]pyridine Ring

Abe et al.



Table 1. (Continued)

a Concentration required to inhibit specific binding of [3H]BK (0.06 nM) to B receptors in guinea pig ileum membrane preparations by 2 50%. Values are expressed as the average of at least three determinations, with variation in individual values of

A Novel Class of Orally Active Non-Peptide Bradykinin B2

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