Angiotensin II

Dose-response curves to angiotensin I (1 ng-pg) in normoxia showed greatly enhanced pressor responses in chronically hypoxic compared with normal rats, probably attributable to increased sensitivity to angiotensin II rather than enhanced conversion of angiotensin I to angiotensin n (Russell et al. 1990). Captopril caused a proportionate reduction in responses in both groups of rats. 

The disclosure by Takeda Chemical Industries, Ltd., of a series of l-benzylimidazole-5-acetic acid-based All antagonists (e.g., 10-12) captured 

Ultimately, through additional SAR exploration and modification of this new lead, DuPont Merck researchers were able to transform their structure into DuP 753 1 (Losartan, 14), a potent, competitive, orally active. All antagonist 

Also starting from the benzylimidazole series reported by the Takeda group, researchers from SmithKline Beecham Pharmaceuticals - similarly postulated that these compounds were mimicking some of the same, critical binding elements used by All when binding to its receptor. However, the SmithKline Beecham scientists made more extensive use of this hypothesis as part of their design efforts. 

A molecular overlay was generated in which the N-benzyl and carboxy groups of the Takeda compound corresponded to the Tyr-4 side chain and the 

As a result of an overlay comparison of SK F 108566 with a representative biphenyltetrazole nonpeptidic antagonist (e.g., see 14), SmithKline Beecham scientists suggested that these two series of antagonists may be binding to the All receptor in a different manner. A discussion of alternate possibilities 

---

Glucocorticoids have been shown to inhibit gene transcription of other proteins involved in the inflammatory process, including the key inflammation mediators called cytokines (IL-1, IL3—6, IL8, GM-CSF, TNFa) (10,58,63—65). Steroids have been also shown to suppress the formation of cytokine receptors (10) dexamethasone, in particular, downregulates gene transcription of angiotensin II type 2 receptors (66). 

The primary effects of angiotensin II ate (/) produciag vasoconstriction directiy or iadirectiy through activation of the adrenergic nervous system ... 

Indapamide has been shown to possess diuretic and iadependent vasodilatory effects (16). It lowers the elevated blood pressure and reduces total peripheral resistance without an iacrease ia heart rate. ladapamide antagoni2es the vasocoastrictiag effects of the catecholamiaes and angiotensin II (16), a property not shared by other thia2ide-type diuretics. Tripamide is also reported to have direct vasodilatory effects (13). 

The Paal-Knorr furan synthesis can also be used to prepare 2,5-arylalkylfurans, as illustrated in the following example. Salimbeni produced furan 29 from dione 28 and subsequently used the furan as an intermediate for the production of angiotensin II receptor antagonists. ... 

A patent (95JAP07196655) deseribed the preparation of a 2//-indazole derivative of speeifie formula 109 useful as a therapeutie agent for a eireulatory disease sueh as hypertension, having angiotensin II antagonism and antihypertensive aetion. In formula 109 r = lower alkyl or alkenyl R, R = H, halogen, lower... 

Alkoxy-3- 4-[2-(5-tetrazolyl)phenyl]phenylmethyl -4/f-pyrido[l,2-a]py-rimidin-4-ones 417 exhibited potential angiotensin II receptor antagonistic activities (94BMCL183). 

Draw the structure of the PTH derivative that would be formed on Edman degradation of angiotensin II (Problem 26.12). 

Give an mRNA sequence that will code for the synthesis of angiotensin II. 

AbdAlla, S., Lother, H., el Massiery, A., and Quitterer, U. (2001). Increased AT(1) receptor dimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nature Med. 7 1003-1009. 

Chymase (mast cell protease type II), a chymotrypsin-like protease, is a serine protease found in mucosal mast cells, which catalyzes the conversion of angiotensin I to angiotensin II and of big endothelin 1 (ET1) to ET1 (1-31). 

---