Prashant Naik

Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists—A perspective

Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT(1) and AT(2). Angiotensin II through AT(1) receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT(1)) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT(1) antagonists are based on modifications of losartan structure, the first clinically used AT(1) antagonist. In this review, a comprehensive presentation of the literature on AT(1) receptor antagonists has been given.

Pyrido[1,2-a]pyrimidin-4-ones as antiplasmodial falcipain-2 inhibitors

Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is a promising target for antimalarial chemotherapy and inhibition of this protease affects the growth of parasite adversely. A series of pyrido[1,2-a]pyrimidin-4-ones were synthesized and evaluated for their in vitro FP-2 inhibitory potential. Compounds (14,17) showed excellent FP-2 inhibition and can serve as lead compounds for further development of potent FP-2 inhibitors as potential antimalarial drugs.

Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review.

Introduction: There is an urgent need to discover new antimalarial drugs due to emergence of resistance in the parasite to the existing drugs. Malarial cysteine proteases falcipin-2 (FP-2) and falcipain-3 (FP-3) are attractive targets for antimalarial chemotherapy. The structures and functions of FP-2/3, their binding domains and their interactions with small- and macro-molecules are well studied. These studies could provide important insight into rational designing of FP inhibitors as potential antimalarial drugs. Areas covered: This review is focused on a selection of interesting patents published during 1999 – 2011 on peptidic and nonpeptidic chemotypes of the FP-2/FP-3 inhibitors. Expert opinion: It is a known fact that malaria is a serious health problem worldwide due to the emergence of resistant strains. Hence, development of novel, potent and affordable antimalarial drugs devoid of side effects is of great significance and in great demand. FPs, the malarial cysteine proteases are potential targets for development of new antimalarial drugs. Assessing the available literature on FP-2/3 and their inhibitors it could be speculated that these inhibitors have the potential to enter the clinical stages of development for the treatment of malaria in the years to come.

Cytotoxic potential of novel 6,7-dimethoxyquinazolines

Herein, we report the synthesis and cytotoxicity of a series of substituted 6,7-dimethoxyquinazoline derivatives. The cytotoxic activity of all synthesized compounds has been evaluated against HCT116p53(+/+) and HCT116p53(-/-) colon cancer cells and a HEY ovarian cancer cell line naturally resistant to cisplatin. Nine of the tested compounds showed significant cytotoxicity in all cell lines at 10μM. The most promising derivative (7c) showed IC(50)values of 0.7 and 1.7μM in the two colon cancer cell lines.

Revelation on the potency of α1 -blockers – parallel blockade of angiotensin II receptor: A new finding

Context: The problem of hypertension has gained enormous proportions in the past decade. Multifactorial etiology and complex pathophysiology of the disease has rendered the treatment of the disease a hard task. Sympathetic nervous system and the renin–angiotensin–aldosterone system are primary contributors of blood pressure homeostasis. Objective: Structural similarities were identified among AT1 and α1-antagonists, initiating a speculation that α1-antagonists could possibly block the AT1 receptor and vice-versa. Methods: To corroborate this speculation, we screened prototypical α1-antagonists such as prazosin, doxazosin, and terazosin for antagonism of angiotensin II on rat aortic strips. We also examined the AT1 antagonists losartan, valsartan, and olmesartan for their possible antagonistic effect, on contractions of rat aortic strips induced by phenylephrine. Results: To our astonishment, we found that prazosin and its analogs which have been reported to have α1-antagonistic activity only, were able to shift concentration response curves of angiotensin II. Conclusion: Our findings suggest that the potent antihypertensive effect of prazosin-type α1-antagonists is not purely due to α1-receptor blocking activity of these compounds but also due to blockade of AT1 receptors. This finding may lead to the development of more potent dual inhibitors which would prove to be of immense value in the control of the scourge of hypertension.

Enhancing Skin Permeation of Biphenylacetic Acid (BPA) Using Salt Formation with Organic and Alkali Metal Bases

In the present study, a series of organic and alkali metal salts of biphenylacetic acid (BPA) have been prepared and evaluated in vitro for percutaneous drug delivery. The physicochemical properties of BPA salts were determined using solubility measurements, DSC, and IR. The DSC thermogram and FTIR spectra confirmed the salt formation with organic and alkali metal bases. Among the series, salts with organic amines (ethanolamine, diethanolamine, triethanolamine, and diethylamine) had lowered melting points while the alkali metal salt (sodium) had a higher melting point than BPA. The in vitro study showed that salt formation improves the physicochemical properties of BPA, leading to improved permeability through the skin. Amongst all the prepared salts, ethanolamine salt (1b) showed 7.2- and 5.4-fold higher skin permeation than the parent drug at pH 7.4 and 5.0, respectively, using rat skin.

Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism

Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α1-blockers and AII-antagonists it was planned to develop dual α1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α1- and AII-antagonists on rat aortic strips for the blockade of known α1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α1- as well as AII-receptor antagonists.

Protective effects of MCR-1329, a dual α1 and angII receptor antagonist, in mineralocorticoid-induced hypertension

BACKGROUND With the prototypical structures of losartan and prazosin as the axis of our research, MCR-1329 emerged as a potential designed multiple ligand from a series of compounds designed to possess dual antagonistic activity on the α1 and AT1 receptor. After confirming the activity of MCR-1329 in in vitro and acute in vivo models, the present study was undertaken to determine the efficacy of MCR-1329 in a mammalian test system. METHODS A rat model of deoxycorticosterone acetate (DOCA)-salt induced renal hypertension following unilateral nephrectomy was utilized to determine the effect of MCR-1329. For mechanistic evaluations, MCR-1329 was evaluated on rat aortic strips in vitro and on rat aortic smooth muscle cells to determine the role of MCR-1329 on phosphoinositide 3 kinase (PI3K) signaling. RESULTS Results of the study showed that MCR-1329 prevents development of arterial hypertension. It was also observed that MCR-1329 upheld the intimal structures of major arteries like the thoracic aorta. Acetylcholine (Ach)-mediated relaxation remained intact in arteries from MCR-1329 treated animals. It was observed that MCR-1329 partially prevents Thr-308 phosphorylation of Akt following ligand-mediated receptor stimulation in vascular smooth muscle cells. Addition of LY294002 to the reaction medium caused a near-complete inhibition of Akt-phosphorylation. This suggested that MCR-1329 elicits its antihypertensive role by blocking activation of receptor-mediated PI3K-Akt downstream signaling as well as through preservation of arterial integrity. CONCLUSIONS MCR-1329 has the potential to be evaluated further for clinical development as a potential antihypertensive agent with multiple mechanisms of action.