Rajan Anand - Academia.edu (original) (raw)
Papers by Rajan Anand
![Research paper thumbnail of Potent, exceptionally selective, orally bioavailable inhibitors of TNF-α Converting Enzyme (TACE): Novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1′ substituents](https://attachments.academia-assets.com/119199280/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry Letters, Mar 1, 2008
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 ... more Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 substituents in conjunction with unique constrained b-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-a Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-a in human whole blood and orally bioavailable.
Bioorganic & Medicinal Chemistry Letters, Mar 1, 2011
We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antago... more We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.
British Journal of Oral & Maxillofacial Surgery, May 1, 2010
Bioorganic & Medicinal Chemistry Letters, Mar 1, 2008
Potent and selective inhibitors of tumor necrosis factor-a converting enzyme (TACE) were discover... more Potent and selective inhibitors of tumor necrosis factor-a converting enzyme (TACE) were discovered with several new heterocyclic P1 0 groups in conjunction with cyclic b-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran b-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC 50 value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-a of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F% > 90%) in rat n-in-1 PK studies.
Experimental Parasitology, Dec 1, 1965
Bioorganic & Medicinal Chemistry Letters, May 1, 2011
Bioorganic & Medicinal Chemistry Letters, Aug 1, 2015
Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series... more Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile.
Journal of Clinical and Scientific Research
Background: Intrathecal nalbuphine is one such opioid, highly lipid soluble with an agonist actio... more Background: Intrathecal nalbuphine is one such opioid, highly lipid soluble with an agonist action at the kappa and antagonist activity at the muopioid receptors, known cardiovascular stability, minimal dose and volume of this drug that can be added to a local anaesthetic agent. Methods: This prospective randomised double-blind study was conducted to evaluate the effects of adding nalbuphine to 0.5% hyperbaric bupivacaine in spinal anaesthesia to know the efficacy, duration of analgesia, incidence of side effects and complications. Sixty American Society of Anesthesiologists (ASA) grade I and II patients were randomly allocated to Group A and Group B of 30 each who received 0.4 mL (0.4 mg) of nalbuphine and 0.4 mL of normal saline added to 3 mL (15 mg) of 0.5% hyperbaric bupivacaine, respectively. Intraoperative haemodynamic parameters, onset, duration of sensory and motor block, visual analogue scale (VAS) score, duration of effective analgesia and possible side effects were monitored and compared. Results: There was no statistically significant difference in the haemodynamic parameters, onset of blockade, duration of motor blockade and side effects. However, in two-segment regression, time of sensory blockade, duration of effective analgesia and VAS scores in Group A were found statistically significantly higher (P < 0.001) compared to Group B. Conclusions: Intrathecal nalbuphine used as adjuvant to bupivacaine prolongs duration of effective analgesia, without any significant side effects with stable haemodynamic parameters.
Indian Journal of Otolaryngology and Head & Neck Surgery, 2021
Carcinoma tongue is one of the commonest cancer of head and neck in India. Various pedicled and f... more Carcinoma tongue is one of the commonest cancer of head and neck in India. Various pedicled and free flaps have been used to reconstruct the tongue defect following glossectomies. In this era of free flaps various loco- regional pedicled flaps have been overlooked and infrahyoid flap is one of them. This flap meets the functional and cosmetic acceptance of the tongue defect reconstruction with minimal morbidity to the donor site. This paper presents author’s experience of using infrahyoid flap in 10 patients of carcinoma tongue. In all the patient’s tongue defect was closed with the infrahyoid flap, in 1 case flap necrosed fully and in 1 partially. Functional outcome and quality of life in all the patients were acceptable.
La presente invention concerne des composes d'inhibiteurs de la tyrosine kinase de Bruton (Bt... more La presente invention concerne des composes d'inhibiteurs de la tyrosine kinase de Bruton (Btk) selon la formule I ou des sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne la formule (I) ou un sel pharmaceutiquement acceptable de celle-ci ou des compositions pharmaceutiques comprenant ces composes et leur utilisation dans un traitement. En particulier, la presente invention concerne l'utilisation de composes d'inhibiteurs de Btk dans le traitement de troubles medies par la Btk.
![Research paper thumbnail of Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes](https://attachments.academia-assets.com/117403192/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry Letters, 2020
Journal of cardiac surgery, Jan 12, 2017
and may involve the atrium, ventricles, valves, and pulmonary arteries. 1-3 We present images of ... more and may involve the atrium, ventricles, valves, and pulmonary arteries. 1-3 We present images of an angiosarcoma involving the right atrium and right ventricle.
![Research paper thumbnail of Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis](https://attachments.academia-assets.com/117403194/thumbnails/1.jpg)
](Bioorganic & medicinal chemistry letters, Aug 18, 2017
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, ex... more 8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Bioorganic & Medicinal Chemistry Letters, 2017
Bioorganic & Medicinal Chemistry Letters, Mar 1, 2008
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 ... more Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 substituents in conjunction with unique constrained b-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-a Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-a in human whole blood and orally bioavailable.
Bioorganic & Medicinal Chemistry Letters, Mar 1, 2011
We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antago... more We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.
British Journal of Oral & Maxillofacial Surgery, May 1, 2010
Bioorganic & Medicinal Chemistry Letters, Mar 1, 2008
Potent and selective inhibitors of tumor necrosis factor-a converting enzyme (TACE) were discover... more Potent and selective inhibitors of tumor necrosis factor-a converting enzyme (TACE) were discovered with several new heterocyclic P1 0 groups in conjunction with cyclic b-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran b-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC 50 value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-a of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F% > 90%) in rat n-in-1 PK studies.
Experimental Parasitology, Dec 1, 1965
Bioorganic & Medicinal Chemistry Letters, May 1, 2011
Bioorganic & Medicinal Chemistry Letters, Aug 1, 2015
Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series... more Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile.
Journal of Clinical and Scientific Research
Background: Intrathecal nalbuphine is one such opioid, highly lipid soluble with an agonist actio... more Background: Intrathecal nalbuphine is one such opioid, highly lipid soluble with an agonist action at the kappa and antagonist activity at the muopioid receptors, known cardiovascular stability, minimal dose and volume of this drug that can be added to a local anaesthetic agent. Methods: This prospective randomised double-blind study was conducted to evaluate the effects of adding nalbuphine to 0.5% hyperbaric bupivacaine in spinal anaesthesia to know the efficacy, duration of analgesia, incidence of side effects and complications. Sixty American Society of Anesthesiologists (ASA) grade I and II patients were randomly allocated to Group A and Group B of 30 each who received 0.4 mL (0.4 mg) of nalbuphine and 0.4 mL of normal saline added to 3 mL (15 mg) of 0.5% hyperbaric bupivacaine, respectively. Intraoperative haemodynamic parameters, onset, duration of sensory and motor block, visual analogue scale (VAS) score, duration of effective analgesia and possible side effects were monitored and compared. Results: There was no statistically significant difference in the haemodynamic parameters, onset of blockade, duration of motor blockade and side effects. However, in two-segment regression, time of sensory blockade, duration of effective analgesia and VAS scores in Group A were found statistically significantly higher (P < 0.001) compared to Group B. Conclusions: Intrathecal nalbuphine used as adjuvant to bupivacaine prolongs duration of effective analgesia, without any significant side effects with stable haemodynamic parameters.
Indian Journal of Otolaryngology and Head & Neck Surgery, 2021
Carcinoma tongue is one of the commonest cancer of head and neck in India. Various pedicled and f... more Carcinoma tongue is one of the commonest cancer of head and neck in India. Various pedicled and free flaps have been used to reconstruct the tongue defect following glossectomies. In this era of free flaps various loco- regional pedicled flaps have been overlooked and infrahyoid flap is one of them. This flap meets the functional and cosmetic acceptance of the tongue defect reconstruction with minimal morbidity to the donor site. This paper presents author’s experience of using infrahyoid flap in 10 patients of carcinoma tongue. In all the patient’s tongue defect was closed with the infrahyoid flap, in 1 case flap necrosed fully and in 1 partially. Functional outcome and quality of life in all the patients were acceptable.
La presente invention concerne des composes d'inhibiteurs de la tyrosine kinase de Bruton (Bt... more La presente invention concerne des composes d'inhibiteurs de la tyrosine kinase de Bruton (Btk) selon la formule I ou des sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne la formule (I) ou un sel pharmaceutiquement acceptable de celle-ci ou des compositions pharmaceutiques comprenant ces composes et leur utilisation dans un traitement. En particulier, la presente invention concerne l'utilisation de composes d'inhibiteurs de Btk dans le traitement de troubles medies par la Btk.
Bioorganic & Medicinal Chemistry Letters, 2020
Journal of cardiac surgery, Jan 12, 2017
and may involve the atrium, ventricles, valves, and pulmonary arteries. 1-3 We present images of ... more and may involve the atrium, ventricles, valves, and pulmonary arteries. 1-3 We present images of an angiosarcoma involving the right atrium and right ventricle.
Bioorganic & medicinal chemistry letters, Aug 18, 2017
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, ex... more 8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Bioorganic & Medicinal Chemistry Letters, 2017